@article {2024|2168, title = {The characterization of ancient Methanococcales malate dehydrogenases reveals that strong thermal stability prevents unfolding under intense γ-irradiation}, journal = {Mol. Biol. Evol.}, volume = {41}, year = {2024}, abstract = {

Malate dehydrogenases (MalDHs) (EC.1.1.1.37), which are involved in the conversion of oxaloacetate to pyruvate in the tricarboxylic acid cycle, are a relevant model for the study of enzyme evolution and adaptation. Likewise, a recent study showed that Methanococcales, a major lineage of Archaea, is a good model to study the molecular processes of proteome thermoadaptation in prokaryotes. Here, we use ancestral sequence reconstruction and paleoenzymology to characterize both ancient and extant MalDHs. We observe a good correlation between inferred optimal growth temperatures and experimental optimal temperatures for activity (A-Topt). In particular, we show that the MalDH present in the ancestor of Methanococcales was hyperthermostable and had an A-Topt of 80 \°C, consistent with a hyperthermophilic lifestyle. This ancestor gave rise to two lineages with different thermal constraints: one remained hyperthermophilic, while the other underwent several independent adaptations to colder environments. Surprisingly, the enzymes of the first lineage have retained a thermoresistant behavior (i.e. strong thermostability and high A-Topt), whereas the ancestor of the second lineage shows a strong thermostability, but a reduced A-Topt. Using mutants, we mimic the adaptation trajectory toward mesophily and show that it is possible to significantly reduce the A-Topt without altering the thermostability of the enzyme by introducing a few mutations. Finally, we reveal an unexpected link between thermostability and the ability to resist γ-irradiation-induced unfolding.

}, keywords = {ancestral sequence reconstruction, COaLA evolutionary model, extremophiles, irradiation, reactive oxygen species, thermal adaptation}, author = {Madern, Dominique and Halgand, Fr{\'e}d{\'e}ric and Hou{\'e}e-Levin, Chantal and Dufour, Anne-B{\'e}atrice and Coquille, Sandrine and Ansanay-Alex, Salom{\'e} and S Sacquin-Mora and Brochier-Armanet, C{\'e}line} } @article {2024, title = {A Perspective on the Prospective Use of AI in Protein Structure Prediction}, journal = {J Chem Inf Model}, volume = {64}, year = {2024}, month = {Jan}, pages = {26{\textendash}41}, author = {Versini, R. and Sritharan, S. and Aykac Fas, B. and Tubiana, T. and Aimeur, S. Z. and Henri, J. and Erard, M. and N{\"u}sse, O. and Andreani, J. and Baaden, M. and Fuchs, P. and Galochkina, T. and Chatzigoulas, A. and Cournia, Z. and Santuz, H. and S Sacquin-Mora and Taly, A.} } @article {2023|2164, title = {Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 May 05}, pages = {2594}, abstract = {

Brown adipose tissue expresses uncoupling protein 1 (UCP1), which dissipates energy as heat, making it a target for treating metabolic disorders. Here, we investigate how purine nucleotides inhibit respiration uncoupling by UCP1. Our molecular simulations predict that GDP and GTP bind UCP1 in the common substrate binding site in an upright orientation, where the base moiety interacts with conserved residues R92 and E191. We identify a triplet of uncharged residues, F88/I187/W281, forming hydrophobic contacts with nucleotides. In yeast spheroplast respiration assays, both I187A and W281A mutants increase the fatty acid-induced uncoupling activity of UCP1 and partially suppress the inhibition of UCP1 activity by nucleotides. The F88A/I187A/W281A triple mutant is overactivated by fatty acids even at high concentrations of purine nucleotides. In simulations, E191 and W281 interact with purine but not pyrimidine bases. These results provide a molecular understanding of the selective inhibition of UCP1 by purine nucleotides.

}, keywords = {Adipose Tissue, Brown, Fatty Acids, Ion Channels, Membrane Proteins, Mitochondrial Proteins, Purine Nucleotides, Saccharomyces cerevisiae, Uncoupling Protein 1}, issn = {2041-1723}, doi = {10.1038/s41467-023-38219-9}, author = {Gagelin, Antoine and Largeau, Corentin and Masscheleyn, Sandrine and Piel, Mathilde S and Calder{\'o}n-Mora, Daniel and Bouillaud, Fr{\'e}d{\'e}ric and J{\'e}r{\^o}me H{\'e}nin and Miroux, Bruno} } @article {2023|2165, title = {Unwrapping NPT Simulations to Calculate Diffusion Coefficients}, journal = {Journal of Chemical Theory and Computation}, volume = {19}, year = {2023}, pages = {3406{\textendash}3417}, doi = {10.1021/acs.jctc.3c00308}, url = {https://doi.org/10.1021/acs.jctc.3c00308}, author = {Jakob T{\'o}mas Bullerjahn and S{\"o}ren von B{\"u}low and Maziar Heidari and J{\'e}r{\^o}me H{\'e}nin and Gerhard Hummer} } @article {2022|2157, title = {Consistent Picture of Phosphate{\textendash}Divalent Cation Binding from Models with Implicit and Explicit Electronic Polarization}, journal = {J. Phys. Chem. B}, volume = {126}, year = {2022}, month = {05/2022}, pages = {4022-4034}, doi = {10.1021/acs.jpcb.2c01158}, url = {https://pubs.acs.org/doi/full/10.1021/acs.jpcb.2c01158}, author = {Julie Puyo-Fourtine and Marie Juill{\'e} and J{\'e}r{\^o}me H{\'e}nin and Carine Clavagu{\'e}ra and Elise Dubou{\'e}-Dijon} } @article {2022|2161, title = {Enhanced Sampling Methods for Molecular Dynamics Simulations [Article v1.0]}, journal = {Living Journal of Computational Molecular Science}, volume = {4}, year = {2022}, month = {Dec.}, pages = {1583}, abstract = {

Enhanced sampling algorithms have emerged as powerful methods to extend the utility of molecular dynamics simulations and allow the sampling of larger portions of the configuration space of complex systems in a given amount of simulation time. This review aims to present the unifying principles of and differences between many of the computational methods currently used for enhanced sampling in molecular simulations of biomolecules, soft matter and molecular crystals. In fact, despite the apparent abundance and divergence of such methods, the principles at their core can be boiled down to a relatively limited number of statistical and physical concepts. To enable comparisons, the various methods are introduced using similar terminology and notation. We then illustrate in which ways many different methods combine features of a relatively small number of the same enhanced sampling concepts. This review is intended for scientists with an understanding of the basics of molecular dynamics simulations and statistical physics who want a deeper understanding of the ideas that underlie various enhanced sampling methods and the relationships between them. This living review is intended to be updated to continue to reflect the wealth of sampling methods as they continue to emerge in the literature.

}, doi = {10.33011/livecoms.4.1.1583}, url = {https://livecomsjournal.org/index.php/livecoms/article/view/v4i1e1583}, author = {J{\'e}r{\^o}me H{\'e}nin and Leli{\`e}vre, Tony and Shirts, Michael R. and Valsson, Omar and Delemotte, Lucie} } @article {2022|2152, title = {Human Learning for Molecular Simulations: The Collective Variables Dashboard in VMD.}, journal = {J Chem Theory Comput}, volume = {18}, year = {2022}, month = {2022 Mar 08}, pages = {1945-1956}, abstract = {

The Collective Variables Dashboard is a software tool for real-time, seamless exploration of molecular structures and trajectories in a customizable space of collective variables. The Dashboard arises from the integration of the Collective Variables Module (also known as Colvars) with the visualization software VMD, augmented with a fully discoverable graphical interface offering interactive workflows for the design and analysis of collective variables. Typical use cases include a priori design of collective variables for enhanced sampling and free energy simulations as well as analysis of any type of simulation or collection of structures in a collective variable space. A combination of those cases commonly occurs when preliminary simulations, biased or unbiased, reveal that an optimized set of collective variables is necessary to improve sampling in further simulations. Then the Dashboard provides an efficient way to intuitively explore the space of likely collective variables, validate them on existing data, and use the resulting collective variable definitions directly in further biased simulations using the Collective Variables Module. Visualization of biasing energies and forces is proposed to help analyze or plan biased simulations. We illustrate the use of the Dashboard on two applications: discovering coordinates to describe ligand unbinding from a protein binding site and designing volume-based variables to bias the hydration of a transmembrane pore.

}, issn = {1549-9626}, doi = {10.1021/acs.jctc.1c01081}, author = {J{\'e}r{\^o}me H{\'e}nin and Lopes, Laura J S and Giacomo Fiorin} } @article {2022|2153, title = {Multiscale Computational Study of the Conformation of the Full-Length Intrinsically Disordered Protein MeCP2.}, journal = {J Chem Inf Model}, volume = {62}, year = {2022}, month = {2022 02 28}, pages = {958-970}, abstract = {

The malfunction of the methyl-CpG binding protein 2 (MeCP2) is associated with the Rett syndrome, one of the most common causes of cognitive impairment in females. MeCP2 is an intrinsically disordered protein (IDP), making its experimental characterization a challenge. There is currently no structure available for the full-length MeCP2 in any of the databases, and only the structure of its MBD domain has been solved. We used this structure to build a full-length model of MeCP2 by completing the rest of the protein via ab initio modeling. Using a combination of all-atom and coarse-grained simulations, we characterized its structure and dynamics as well as the conformational space sampled by the ID and transcriptional repression domain (TRD) domains in the absence of the rest of the protein. The present work is the first computational study of the full-length protein. Two main conformations were sampled in the coarse-grained simulations: a globular structure similar to the one observed in the all-atom force field and a two-globule conformation. Our all-atom model is in good agreement with the available experimental data, predicting amino acid W104 to be buried, amino acids R111 and R133 to be solvent-accessible, and having a 4.1\% α-helix content, compared to the 4\% found experimentally. Finally, we compared the model predicted by AlphaFold to our Modeller model. The model was not stable in water and underwent further folding. Together, these simulations provide a detailed (if perhaps incomplete) conformational ensemble of the full-length MeCP2, which is compatible with experimental data and can be the basis of further studies, e.g., on mutants of the protein or its interactions with its biological partners.

}, issn = {1549-960X}, doi = {10.1021/acs.jcim.1c01354}, author = {Ch{\'a}vez-Garc{\'\i}a, Cecilia and J{\'e}r{\^o}me H{\'e}nin and Karttunen, Mikko} } @article {2022|2160, title = {Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation}, journal = {Nature Communications}, volume = {13}, year = {2022}, doi = {10.1038/s41467-022-34813-5}, url = {https://doi.org/10.1038/s41467-022-34813-5}, author = {John T. Petroff and Noah M. Dietzen and Ezry Santiago-McRae and Brett Deng and Maya S. Washington and Lawrence J. Chen and K. Trent Moreland and Zengqin Deng and Michael Rau and James A. J. Fitzpatrick and Peng Yuan and Thomas T. Joseph and J{\'e}r{\^o}me H{\'e}nin and Grace Brannigan and Wayland W. L. Cheng} } @article {2022|2151, title = {Symmetry-Adapted Restraints for Binding Free Energy Calculations.}, journal = {J Chem Theory Comput}, year = {2022}, month = {2022 Mar 01}, abstract = {

Binding free energy calculations rely critically on a precise definition of the bound state and well-designed ligand restraints to ensure that binding free energy calculations converge rapidly and yield estimates of well-defined thermodynamic quantities. The distance-to-bound-configuration (DBC) is a single variable that can precisely delineate the bound state of a ligand including translational, rotational and conformational degrees of freedom and has been successfully used to capture binding modes with complex geometries. DBC is defined as the root-mean-square deviation (RMSD) of ligand coordinates in the frame of reference of the binding site. In the special case where the ligand features symmetry-equivalent atoms, a standard RMSD arbitrarily distinguishes equivalent poses, mixing equivalent and nonequivalent degrees of freedom, and preventing the precise delineation of the bound state ensemble, which negates the benefits of defining a flat-bottom binding restraint. To remedy this, we introduce a symmetry-adapted DBC coordinate where the RMSD is minimized over permutations of equivalent ligand atoms. This coordinate is implemented in a portable software library, the Collective Variables Module. We tested the approach by computing the absolute binding free energy of benzene to the engineered site of a mutant lysozyme (L99A/M102H) using alchemical free energy perturbation. We found that the symmetry-adapted restraint leads to well-behaved convergence of both the decoupling free energy in the binding site and the restrained free energy in the gas phase, recovering the affinity computed using a classic center-of-mass restraint. Thus, symmetry-adapted DBC seamlessly generalizes the benefits of DBC restraints to the case of symmetric ligands. The underlying symmetric RMSD coordinate can also be used for analyzing or biasing simulations in other contexts than affinity predictions.

}, issn = {1549-9626}, doi = {10.1021/acs.jctc.1c01235}, author = {Ebrahimi, Mina and J{\'e}r{\^o}me H{\'e}nin} } @article {2021|2148, title = {Building intuition for binding free energy calculations: Bound state definition, restraints, and symmetry}, journal = {The Journal of Chemical Physics}, volume = {154}, year = {2021}, pages = {204101}, doi = {10.1063/5.0046853}, url = {https://doi.org/10.1063/5.0046853}, author = {Elise Dubou{\'e}-Dijon and J{\'e}r{\^o}me H{\'e}nin} } @article {2021|2149, title = {Fast and Accurate Multidimensional Free Energy Integration.}, journal = {J Chem Theory Comput}, volume = {17}, year = {2021}, month = {2021 Nov 09}, pages = {6789-6798}, abstract = {

Enhanced sampling and free energy calculation algorithms of the thermodynamic integration family (such as the adaptive biasing force (ABF) method) are not based on the direct computation of a free energy surface but rather of its gradient. Integrating the free energy surface is nontrivial in dimensions higher than one. Here, the author introduces a flexible, portable implementation of a Poisson equation formalism to integrate free energy surfaces from estimated gradients in dimensions 2 and 3 using any combination of periodic and nonperiodic (Neumann) boundary conditions. The algorithm is implemented in portable C++ and provided as a standalone tool that can be used to integrate multidimensional gradient fields estimated on a grid using any algorithm, such as umbrella integration as a post-treatment of umbrella sampling simulations. It is also included in the implementation of ABF (and its extended-system variant eABF) in the Collective Variables Module, enabling the seamless computation of multidimensional free energy surfaces within ABF and eABF simulations. A Python-based analysis toolchain is provided to easily plot and analyze multidimensional ABF simulation results, including metrics to assess their convergence. The Poisson integration algorithm can also be used to perform Helmholtz decomposition of noisy gradient estimates on the fly, resulting in an efficient implementation of the projected ABF (pABF) method proposed by Leli{\'e}vre and co-workers. In numerical tests, pABF is found to lead to faster convergence with respect to ABF in simple cases of low intrinsic dimension but seems detrimental to convergence in a more realistic case involving degenerate coordinates and hidden barriers due to slower exploration. This suggests that variance reduction schemes do not always yield convergence improvements when applied to enhanced sampling methods.

}, issn = {1549-9626}, doi = {10.1021/acs.jctc.1c00593}, author = {J{\'e}r{\^o}me H{\'e}nin} } @article {2021|2147, title = {Mechanistic Insights on Heme-to-Heme Transmembrane Electron Transfer Within NADPH Oxydases From Atomistic Simulations.}, journal = {Front Chem}, volume = {9}, year = {2021}, month = {2021}, pages = {650651}, abstract = {

NOX5 is a member of the NADPH oxidase family which is dedicated to the production of reactive oxygen species. The molecular mechanisms governing transmembrane electron transfer (ET) that permits to shuttle electrons over the biological membrane have remained elusive for a long time. Using computer simulations, we report conformational dynamics of NOX5 embedded within a realistic membrane environment. We assess the stability of the protein within the membrane and monitor the existence of cavities that could accommodate dioxygen molecules. We investigate the heme-to-heme electron transfer. We find a reaction free energy of a few tenths of eV (ca. -0.3 eV) and a reorganization free energy of around 1.1 eV (0.8 eV after including electrostatic induction corrections). The former indicates thermodynamically favorable ET, while the latter falls in the expected values for transmembrane inter-heme ET. We estimate the electronic coupling to fall in the range of the μeV. We identify electron tunneling pathways showing that not only the W378 residue is playing a central role, but also F348. Finally, we reveal the existence of two connected Obinding pockets near the outer heme with fast exchange between the two sites on the nanosecond timescale. We show that when the terminal heme is reduced, O binds closer to it, affording a more efficient tunneling pathway than when the terminal heme is oxidized, thereby providing an efficient mechanism to catalyze superoxide production in the final step. Overall, our study reveals some key molecular mechanisms permitting reactive oxygen species production by NOX5 and paves the road for further investigation of ET processes in the wide family of NADPH oxidases by computer simulations.

}, issn = {2296-2646}, doi = {10.3389/fchem.2021.650651}, author = {Wu, Xiaojing and J{\'e}r{\^o}me H{\'e}nin and Baciou, Laura and Marc Baaden and Cailliez, Fabien and de la Lande, Aur{\'e}lien} } @article {2020|2145, title = {Binding of divalent cations to acetate: molecular simulations guided by Raman spectroscopy}, journal = {Phys. Chem. Chem. Phys.}, volume = {22}, year = {2020}, pages = {24014-24027}, chapter = {24014}, abstract = {

In spite of the biological importance of the binding of Zn2+, Ca2+, and Mg2+ to the carboxylate group, cation\–acetate binding affinities and binding modes remain actively debated. Here, we report the first use of Raman multivariate curve resolution (Raman-MCR) vibrational spectroscopy to obtain self-consistent free and bound metal acetate spectra and one-to-one binding constants, without the need to invoke any a priori assumptions regarding the shapes of the corresponding vibrational bands. The experimental results, combined with classical molecular dynamics simulations with a force field effectively accounting for electronic polarization via charge scaling and ab initio simulations, indicate that the measured binding constants pertain to direct (as opposed to water separated) ion pairing. The resulting binding constants do not scale with cation size, as the binding constant to Zn2+ is significantly larger than that to either Mg2+ or Ca2+, although Zn2+ and Mg2+ have similar radii that are about 25\% smaller than Ca2+. Remaining uncertainties in the metal acetate binding free energies are linked to fundamental ambiguities associated with identifying the range of structures pertaining to non-covalently bound species.

}, doi = {10.1039/D0CP02987D}, url = {https://pubs.rsc.org/en/content/articlelanding/2020/cp/d0cp02987d$\#$!divAbstract}, author = {Mendes de Oliveira, Denilson and Samual R. Zukowski and Vladimir Palivec and J{\'e}r{\^o}me H{\'e}nin and Hector Martinez-Seara and Dor Ben-Amotz and Pavel Jungwirth and Elise Dubou{\'e}-Dijon} } @article {2020|2125, title = {Impact of the Astaxanthin, Betanin, and EGCG Compounds on Small Oligomers of Amyloid Aβ Peptide.}, journal = {J Chem Inf Model}, volume = {60}, year = {2020}, month = {2020 Mar 23}, pages = {1399-1408}, abstract = {

There is experimental evidence that the astaxanthin, betanin, and epigallocatechin-3-gallate (EGCG) compounds slow down the aggregation kinetics and the toxicity of the amyloid-β (Aβ) peptide. How these inhibitors affect the self-assembly at the atomic level remains elusive. To address this issue, we have performed for each ligand atomistic replica exchange molecular dynamic (REMD) simulations in an explicit solvent of the Aβ trimer from the U-shape conformation and MD simulations starting from Aβ dimer and tetramer structures characterized by different intra- and interpeptide conformations. We find that the three ligands have similar binding free energies on small Aβ oligomers but very distinct transient binding sites that will affect the aggregation of larger assemblies and fibril elongation of the Aβ peptide.

}, issn = {1549-960X}, doi = {10.1021/acs.jcim.9b01074}, author = {Minh Hung, Huynh and Nguyen, Minh Tho and Tran, Phuong-Thao and Truong, Vi Khanh and Chapman, James and Quynh Anh, Le Huu and Philippe Derreumaux and Vu, Van V and Ngo, Son Tung} } @article {2020|2142, title = {Scalable molecular dynamics on CPU and GPU architectures with NAMD}, journal = {The Journal of Chemical Physics}, volume = {153}, year = {2020}, chapter = {044130}, abstract = {

NAMD is a molecular dynamics program designed for high-performance simulations of very large biological objects on CPU- and GPU-based architectures. NAMD offers scalable performance on petascale parallel supercomputers consisting of hundreds of thousands of cores, as well as on inexpensive commodity clusters commonly found in academic environments. It is written in C++ and leans on Charm++ parallel objects for optimal performance on low-latency architectures. NAMD is a versatile, multipurpose code that gathers state-of-the-art algorithms to carry out simulations in apt thermodynamic ensembles, using the widely popular CHARMM, AMBER, OPLS, and GROMOS biomolecular force fields. Here, we review the main features of NAMD that allow both equilibrium and enhanced-sampling molecular dynamics simulations with numerical efficiency. We describe the underlying concepts utilized by NAMD and their implementation, most notably for handling long-range electrostatics; controlling the temperature, pressure, and pH; applying external potentials on tailored grids; leveraging massively parallel resources in multiple-copy simulations; and hybrid quantum-mechanical/molecular-mechanical descriptions. We detail the variety of options offered by NAMD for enhanced-sampling simulations aimed at determining free-energy differences of either alchemical or geometrical transformations and outline their applicability to specific problems. Last, we discuss the roadmap for the development of NAMD and our current efforts toward achieving optimal performance on GPU-based architectures, for pushing back the limitations that have prevented biologically realistic billion-atom objects to be fruitfully simulated, and for making large-scale simulations less expensive and easier to set up, run, and analyze. NAMD is distributed free of charge with its source code at www.ks.uiuc.edu.

}, keywords = {NAMD}, doi = {10.1063/5.0014475}, url = {https://aip.scitation.org/doi/10.1063/5.0014475}, author = {James Phillips and David Hardy and Julio Maia and John Stone and Joao Ribeiro and Rafael Bernardi and Ronak Buch and Giacomo Fiorin and J{\'e}r{\^o}me H{\'e}nin and Wei Jiang and Ryan McGreevy and Melo, Marcelo Cardoso dos Reis and Brian Radak and Robert Skeel and Abhishek Singharoy and Yi Wang and Benoit Roux and Aleksei Aksimentiev and Zan Luthey-Schulten and Laxmikant Kale and Klaus Schulten and Christophe Chipot and Emad Tajkhorshid} } @article {2020|2141, title = {Water dynamics at electrified graphene interfaces: a jump model perspective}, journal = {Phys Chem Chem Phys}, year = {2020}, month = {Mar}, abstract = {

The reorientation dynamics of water at electrified graphene interfaces was recently shown [J. Phys. Chem. Lett., 2020, 11, 624-631] to exhibit a surprising and strongly asymmetric behavior: positive electrode potentials slow down interfacial water reorientation, while for increasingly negative potentials water dynamics first accelerates before reaching an extremum and then being retarded for larger potentials. Here we use classical molecular dynamics simulations to determine the molecular mechanisms governing water dynamics at electrified interfaces. We show that changes in water reorientation dynamics with electrode potential arise from the electrified interfaces\&$\#$39; impacts on water hydrogen-bond jump exchanges, and can be quantitatively described by the extended jump model. Finally, our simulations indicate that no significant dynamical heterogeneity occurs within the water interfacial layer next to the weakly interacting graphene electrode.

}, doi = {10.1039/d0cp00359j}, author = {Zhang, Yiwei and Guillaume Stirnemann and Hynes, James T and Laage, Damien} } @article {2019|2060, title = {Conformational Stability Adaptation of a Double-Stranded RNA-Binding Domain to Transfer RNA Ligand.}, journal = {Biochemistry}, volume = {58}, year = {2019}, month = {2019 May 21}, pages = {2463-2473}, abstract = {

The double-stranded RNA-binding domain (dsRBD) is a broadly distributed domain among RNA-maturing enzymes. Although this domain recognizes dsRNA\&$\#$39;s structures via a conserved canonical structure adopting an α-βββ-α topology, several dsRBDs can accommodate discrete structural extensions expanding further their functional repertoire. How these structural elements engage cooperative communications with the canonical structure and how they contribute to the dsRBD\&$\#$39;s overall folding are poorly understood. Here, we addressed these issues using the dsRBD of human dihydrouridine synthase-2 (hDus2) (hDus2-dsRBD) as a model. This dsRBD harbors N- and C-terminal extensions, the former being directly involved in the recognition of tRNA substrate of hDus2. These extensions engage residues that form a long-range hydrophobic network (LHN) outside the RNA-binding interface. We show by coarse-grain Brownian dynamics that the Nt-extension and its residues F359 and Y364 rigidify the major folding nucleus of the canonical structure via an indirect effect. hDus2-dsRBD unfolds following a two-state cooperative model, whereas both F359A and Y364A mutants, designed to destabilize this LHN, unfold irreversibly. Structural and computational analyses show that these mutants are unstable due to an increase in the dynamics of the two extensions favoring solvent exposure of α2-helix and weakening the main folding nucleus rigidity. This LHN appears essential for maintaining a thermodynamic stability of the overall system and eventually a functional conformation for tRNA recognition. Altogether, our findings suggest that functional adaptability of extended dsRBDs is promoted by a cooperative hydrophobic coupling between the extensions acting as effectors and the folding nucleus of the canonical structure.

}, issn = {1520-4995}, doi = {10.1021/acs.biochem.9b00111}, author = {Bou-Nader, Charles and Pecqueur, Ludovic and Barraud, Pierre and Fontecave, Marc and Tisn{\'e}, Carine and S Sacquin-Mora and Hamdane, Djemel} } @article {2019|2110, title = {Effects of all-atom molecular mechanics force fields on amyloid peptide assembly: the case of aβ16{\textendash}22 dimer}, journal = {Journal of chemical theory and computation}, volume = {15}, year = {2019}, pages = {1440{\textendash}1452}, author = {Man, Viet Hoang and He, Xibing and Philippe Derreumaux and Ji, Beihong and Xie, Xiang-Qun and Phuong Hoang Nguyen and Wang, Junmei} } @article {2019|2080, title = {Highlights from the Faraday Discussion on Artificial Water Channels, Glasgow, UK.}, journal = {Chem Commun (Camb)}, volume = {55}, year = {2019}, month = {2019 Apr 07}, pages = {3853-3858}, issn = {1364-548X}, doi = {10.1039/c9cc90112d}, author = {Barboiu, Mihail and Kumar, Manish and Marc Baaden and Gale, Philip A and Hinds, Bruce J} } @article {2019|2071, title = {Involvement of the GABAA receptor α subunit in the mode of action of etifoxine}, journal = {Pharmacological research}, volume = {145}, year = {2019}, pages = {104250}, author = {Mattei, C{\'e}sar and Antoine Taly and Soualah, Zineb and Saulais, Oph{\'e}lie and Henrion, Daniel and Gu{\'e}rineau, Nathalie C and Verleye, Marc and Legros, Christian} } @article {2019|2119, title = {Stability Effect of Quinary Interactions Reversed by Single Point Mutations}, journal = {Journal of the American Chemical Society}, volume = {141}, year = {2019}, pages = {4660-4669}, doi = {10.1021/jacs.8b13025}, url = {https://doi.org/10.1021/jacs.8b13025}, author = {Gnutt, David and Timr, Stepan and Ahlers, Jonas and K{\"o}nig, Benedikt and Manderfeld, Emily and Heyden, Matthias and Sterpone, Fabio and Ebbinghaus, Simon} } @inbook {2018|2085, title = {Applications to water transport systems: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {389-414}, issn = {1364-5498}, doi = {10.1039/c8fd90022a}, author = {Marc Baaden and Barboiu, Mihail and Borthakur, Manash Pratim and Chen, Chun-Long and Coalson, Rob and Davis, Jeffery and Freger, Viatcheslav and Gong, Bing and H{\'e}lix-Nielsen, Claus and Hickey, Robert and Hinds, Bruce and Hirunpinyopas, Wisit and Horner, Andreas and Hou, Jun-Li and Hummer, Gerhard and Iamprasertkun, Pawin and Kazushi, Kinbara and Kumar, Manish and Legrand, Yves-Marie and Lokesh, Mahesh and Mi, Baoxia and Mitra, Sushanta and Murail, Samuel and Noy, Aleksandr and Nunes, Suzana and Pohl, Peter and Song, Qilei and Song, Woochul and T{\"o}rnroth-Horsefield, Susanna and Vashisth, Harish} } @inbook {2018|2082, title = {Biomimetic water channels: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {205-229}, issn = {1364-5498}, doi = {10.1039/c8fd90020e}, author = {Marc Baaden and Barboiu, Mihail and Bill, Roslyn M and Chen, Chun-Long and Davis, Jeffery and Di Vincenzo, Maria and Freger, Viatcheslav and Fr{\"o}ba, Michael and Gale, Philip A and Gong, Bing and H{\'e}lix-Nielsen, Claus and Hickey, Robert and Hinds, Bruce and Hou, Jun-Li and Hummer, Gerhard and Kumar, Manish and Legrand, Yves-Marie and Lokesh, Mahesh and Mi, Baoxia and Murail, Samuel and Pohl, Peter and Sansom, Mark and Song, Qilei and Song, Woochul and T{\"o}rnroth-Horsefield, Susanna and Vashisth, Harish and V{\"o}gele, Martin} } @article {2018|2046, title = {Controlling Redox Enzyme Orientation at Planar Electrodes}, journal = {Catalysts}, volume = {8}, year = {2018}, abstract = {

Redox enzymes, which catalyze reactions involving electron transfers in living organisms, are very promising components of biotechnological devices, and can be envisioned for sensing applications as well as for energy conversion. In this context, one of the most significant challenges is to achieve efficient direct electron transfer by tunneling between enzymes and conductive surfaces. Based on various examples of bioelectrochemical studies described in the recent literature, this review discusses the issue of enzyme immobilization at planar electrode interfaces. The fundamental importance of controlling enzyme orientation, how to obtain such orientation, and how it can be verified experimentally or by modeling are the three main directions explored. Since redox enzymes are sizable proteins with anisotropic properties, achieving their functional immobilization requires a specific and controlled orientation on the electrode surface. All the factors influenced by this orientation are described, ranging from electronic conductivity to efficiency of substrate supply. The specificities of the enzymatic molecule, surface properties, and dipole moment, which in turn influence the orientation, are introduced. Various ways of ensuring functional immobilization through tuning of both the enzyme and the electrode surface are then described. Finally, the review deals with analytical techniques that have enabled characterization and quantification of successful achievement of the desired orientation. The rich contributions of electrochemistry, spectroscopy (especially infrared spectroscopy), modeling, and microscopy are featured, along with their limitations.

}, issn = {2073-4344}, doi = {10.3390/catal8050192}, url = {http://www.mdpi.com/2073-4344/8/5/192}, author = {Hitaishi, Vivek Pratap and Clement, Romain and Bourassin, Nicolas and Marc Baaden and de Poulpiquet, Anne and S Sacquin-Mora and Ciaccafava, Alexandre and Lojou, Elisabeth} } @article {2018|2093, title = {Dystrophin{\textquoteright}s central domain forms a complex filament that becomes disorganized by in-frame deletions.}, journal = {J Biol Chem}, volume = {293}, year = {2018}, month = {2018 05 04}, pages = {6637-6646}, abstract = {

Dystrophin, encoded by the gene, is critical for maintaining plasma membrane integrity during muscle contraction events. Mutations in the gene disrupting the reading frame prevent dystrophin production and result in severe Duchenne muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted dystrophin and result in less severe Becker muscular dystrophy (BMD). Many known BMD deletions occur in dystrophin\&$\#$39;s central domain, generally considered to be a monotonous rod-shaped domain based on the knowledge of spectrin family proteins. However, the effects caused by these deletions, ranging from asymptomatic to severe BMD, argue against the central domain serving only as a featureless scaffold. We undertook structural studies combining small-angle X-ray scattering and molecular modeling in an effort to uncover the structure of the central domain, as dystrophin has been refractory to characterization. We show that this domain appears to be a tortuous and complex filament that is profoundly disorganized by the most severe BMD deletion (loss of exons 45-47). Despite the preservation of large parts of the binding site for neuronal nitric oxide synthase (nNOS) in this deletion, computational approaches failed to recreate the association of dystrophin with nNOS. This observation is in agreement with a strong decrease of nNOS immunolocalization in muscle biopsies, a parameter related to the severity of BMD phenotypes. The structural description of the whole dystrophin central domain we present here is a first necessary step to improve the design of microdystrophin constructs toward the goal of a successful gene therapy for DMD.

}, keywords = {Binding Sites, Dystrophin, Exons, Gene Deletion, Humans, Molecular Docking Simulation, Muscular Dystrophy, Duchenne, Nitric Oxide Synthase Type I, Protein Domains, Reading Frames, Scattering, Small Angle, Solutions, X-Ray Diffraction}, issn = {1083-351X}, doi = {10.1074/jbc.M117.809798}, author = {Delalande, Olivier and Molza, Anne-Elisabeth and Dos Santos Morais, Raphael and Ch{\'e}ron, Ang{\'e}lique and Pollet, {\'E}meline and Raguenes-Nicol, C{\'e}line and Tascon, Christophe and Giudice, Emmanuel and Guilbaud, Marine and Nicolas, Aur{\'e}lie and Bondon, Arnaud and Leturcq, France and Nicolas F{\'e}rey and Marc Baaden and Perez, Javier and Roblin, Pierre and Pi{\'e}tri-Rouxel, France and Hubert, Jean-Fran{\c c}ois and Czjzek, Mirjam and Le Rumeur, Elisabeth} } @article {2018|2094, title = {Holding the Nucleosome Together: A Quantitative Description of the DNA-Histone Interface in Solution.}, journal = {J Chem Theory Comput}, volume = {14}, year = {2018}, month = {2018 Feb 13}, pages = {1045-1058}, abstract = {

The nucleosome is the fundamental unit of eukaryotic genome packaging in the chromatin. In this complex, the DNA wraps around eight histone proteins to form a superhelical double helix. The resulting bending, stronger than anything observed in free DNA, raises the question of how such a distortion is stabilized by the proteic and solvent environments. In this work, the DNA-histone interface in solution was exhaustively analyzed from nucleosome structures generated by molecular dynamics. An original Voronoi tessellation technique, measuring the topology of interacting elements without any empirical or subjective adjustment, was used to characterize the interface in terms of contact area and occurrence. Our results revealed an interface more robust than previously known, combining extensive, long-lived nonelectrostatic and electrostatic interactions between DNA and both structured and unstructured histone regions. Cation accumulation makes the proximity of juxtaposed DNA gyres in the superhelix possible by shielding the strong electrostatic repulsion of the charged phosphate groups. Overall, this study provides new insights on the nucleosome cohesion, explaining how DNA distortions can be maintained in a nucleoprotein complex.

}, keywords = {DNA, Histones, Molecular Dynamics Simulation, Nucleosomes, Solutions, Static Electricity}, issn = {1549-9626}, doi = {10.1021/acs.jctc.7b00936}, author = {Elbahnsi, Ahmad and Retureau, Romain and Marc Baaden and Hartmann, Brigitte and Oguey, Christophe} } @inbook {2018|2084, title = {The modelling and enhancement of water hydrodynamics: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {273-285}, issn = {1364-5498}, doi = {10.1039/c8fd90021c}, author = {Marc Baaden and Borthakur, Manash Pratim and Casanova, Serena and Coalson, Rob and Freger, Viatcheslav and Gonzalez, Miguel and G{\'o}ra, Artur and Hinds, Bruce and Hirunpinyopas, Wisit and Hummer, Gerhard and Kumar, Manish and Lynch, Charlotte and Murail, Samuel and Noy, Aleksandr and Sansom, Mark and Song, Qilei and Vashisth, Harish and V{\"o}gele, Martin} } @article {2018|2129, title = {Probing the quality control mechanism of the twin-arginine translocase with folding variants of a -designed heme protein.}, journal = {J Biol Chem}, volume = {293}, year = {2018}, month = {2018 05 04}, pages = {6672-6681}, abstract = {

Protein transport across the cytoplasmic membrane of bacterial cells is mediated by either the general secretion (Sec) system or the twin-arginine translocase (Tat). The Tat machinery exports folded and cofactor-containing proteins from the cytoplasm to the periplasm by using the transmembrane proton motive force as a source of energy. The Tat apparatus apparently senses the folded state of its protein substrates, a quality-control mechanism that prevents premature export of nascent unfolded or misfolded polypeptides, but its mechanistic basis has not yet been determined. Here, we investigated the innate ability of the model Tat system to recognize and translocate -designed protein substrates with experimentally determined differences in the extent of folding. Water-soluble, four-helix bundle maquette proteins were engineered to bind two, one, or no heme cofactors, resulting in a concomitant reduction in the extent of their folding, assessed with temperature-dependent CD spectroscopy and one-dimensional H NMR spectroscopy. Fusion of the archetypal N-terminal Tat signal peptide of the trimethylamine--oxide (TMAO) reductase (TorA) to the N terminus of the protein maquettes was sufficient for the Tat system to recognize them as substrates. The clear correlation between the level of Tat-dependent export and the degree of heme -induced folding of the maquette protein suggested that the membrane-bound Tat machinery can sense the extent of folding and conformational flexibility of its substrates. We propose that these artificial proteins are ideal substrates for future investigations of the Tat system\&$\#$39;s quality-control mechanism.

}, keywords = {Amino Acid Sequence, Bacterial Proteins, Circular Dichroism, Escherichia coli, Escherichia coli Proteins, Heme-Binding Proteins, Hemeproteins, Membrane Transport Proteins, Methylamines, Models, Molecular, Oxidoreductases, N-Demethylating, Periplasm, Protein Folding, Protein Sorting Signals, Protein Stability, Protein Transport, Proton Magnetic Resonance Spectroscopy, Substrate Specificity, Temperature}, issn = {1083-351X}, doi = {10.1074/jbc.RA117.000880}, author = {Sutherland, George A and Grayson, Katie J and Adams, Nathan B P and Mermans, Daphne M J and Jones, Alexander S and Robertson, Angus J and Auman, Dirk B and Brindley, Amanda A and Sterpone, Fabio and Tuffery, Pierre and Philippe Derreumaux and Dutton, P Leslie and Robinson, Colin and Hitchcock, Andrew and Hunter, C Neil} } @article {2018|2059, title = {A Streamlined, General Approach for Computing Ligand Binding Free Energies and Its Application to GPCR-Bound Cholesterol.}, journal = {Journal of Chemical Theory and Computation}, volume = {14}, year = {2018}, pages = {6560{\textendash}6573}, abstract = {

The theory of receptor-ligand binding equilibria has long been well-established in biochemistry, and was primarily constructed to describe dilute aqueous solutions. Accordingly, few computational approaches have been developed for making quantitative predictions of binding probabilities in environments other than dilute isotropic solution. Existing techniques, ranging from simple automated docking procedures to sophisticated thermodynamics-based methods, have been developed with soluble proteins in mind. Biologically and pharmacologically relevant protein-ligand interactions often occur in complex environments, including lamellar phases like membranes and crowded, nondilute solutions. Here, we revisit the theoretical bases of ligand binding equilibria, avoiding overly specific assumptions that are nearly always made when describing receptor-ligand binding. Building on this formalism, we extend the asymptotically exact Alchemical Free Energy Perturbation technique to quantifying occupancies of sites on proteins in a complex bulk, including phase-separated, anisotropic, or nondilute solutions, using a thermodynamically consistent and easily generalized approach that resolves several ambiguities of current frameworks. To incorporate the complex bulk without overcomplicating the overall thermodynamic cycle, we simplify the common approach for ligand restraints by using a single distance-from-bound-configuration (DBC) ligand restraint during AFEP decoupling from protein. DBC restraints should be generalizable to binding modes of most small molecules, even those with strong orientational dependence. We apply this approach to compute the likelihood that membrane cholesterol binds to known crystallographic sites on three GPCRs (β -adrenergic, 5HT-2B, and μ-opioid) at a range of concentrations. Nonideality of cholesterol in a binary cholesterol:phosphatidylcholine (POPC) bilayer is characterized and consistently incorporated into the interpretation. We find that the three sites exhibit very different affinities for cholesterol: The site on the adrenergic receptor is predicted to be high affinity, with 50\% occupancy for 1:10 CHOL:POPC mixtures. The sites on the 5HT-2B and μ-opioid receptor are predicted to be lower affinity, with 50\% occupancy for 1:10 CHOL:POPC and 1:10 CHOL:POPC, respectively. These results could not have been predicted from the crystal structures alone.

}, issn = {1549-9626}, doi = {10.1021/acs.jctc.8b00447}, author = {Salari, Reza and Joseph, Thomas and Lohia, Ruchi and J{\'e}r{\^o}me H{\'e}nin and Brannigan, Grace} } @inbook {2018|2083, title = {Structure and function of natural proteins for water transport: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {83-95}, keywords = {Molecular Structure, Proteins, Water}, issn = {1364-5498}, doi = {10.1039/c8fd90019a}, author = {Marc Baaden and Barboiu, Mihail and Bill, Roslyn M and Casanova, Serena and Chen, Chun-Long and Conner, Matthew and Freger, Viatcheslav and Gong, Bing and G{\'o}ra, Artur and Hinds, Bruce and Horner, Andreas and Hummer, Gerhard and Kumar, Manish and Lokesh, Mahesh and Mitra, Sushanta and Noy, Aleksandr and Pohl, Peter and Sadet, Aude and Sansom, Mark and T{\"o}rnroth-Horsefield, Susanna and Vashisth, Harish} } @article {2017|2022, title = {ATP hydrolysis provides functions that promote rejection of pairings between different copies of long repeated sequences}, journal = {Nucleic Acids Res}, volume = {45}, year = {2017}, pages = {8448-8462}, abstract = {

During DNA recombination and repair, RecA family proteins must promote rapid joining of homologous DNA. Repeated sequences with \>100 base pair lengths occupy more than 1\% of bacterial genomes; however, commitment to strand exchange was believed to occur after testing ~20-30 bp. If that were true, pairings between different copies of long repeated sequences would usually become irreversible. Our experiments reveal that in the presence of ATP hydrolysis even 75 bp sequence-matched strand exchange products remain quite reversible. Experiments also indicate that when ATP hydrolysis is present, flanking heterologous dsDNA regions increase the reversibility of sequence matched strand exchange products with lengths up to ~75 bp. Results of molecular dynamics simulations provide insight into how ATP hydrolysis destabilizes strand exchange products. These results inspired a model that shows how pairings between long repeated sequences could be efficiently rejected even though most homologous pairings form irreversible products.

}, doi = {10.1093/nar/gkx582}, author = {Danilowicz, Claudia and Hermans, Laura and Coljee, Vincent and Chantal Pr{\'e}vost and Prentiss, Mara} } @article {2017|2021, title = {A membrane-inserted structural model of the yeast mitofusin Fzo1}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 Aug 31}, pages = {10217}, type = {Research Article}, abstract = {

Mitofusins are large transmembrane GTPases of the dynamin-related protein family, and are required for the tethering and fusion of mitochondrial outer membranes. Their full-length structures remain unknown, which is a limiting factor in the study of outer membrane fusion. We investigated the structure and dynamics of the yeast mitofusin Fzo1 through a hybrid computational and experimental approach, combining molecular modelling and all-atom molecular dynamics simulations in a lipid bilayer with site-directed mutagenesis and in vivo functional assays. The predicted architecture of Fzo1 improves upon the current domain annotation, with a precise description of the helical spans linked by flexible hinges, which are likely of functional significance. In vivo site-directed mutagenesis validates salient aspects of this model, notably, the long-distance contacts and residues participating in hinges. GDP is predicted to interact with Fzo1 through the G1 and G4 motifs of the GTPase domain. The model reveals structural determinants critical for protein function, including regions that may be involved in GTPase domain-dependent rearrangements.

}, issn = {2045-2322}, doi = {10.1038/s41598-017-10687-2}, author = {De Vecchis, Dario and Cavellini, Laetitia and Marc Baaden and J{\'e}r{\^o}me H{\'e}nin and Cohen, Micka{\"e}l M and Antoine Taly} } @article {2017|2028, title = {New Coarse Variables for the Accurate Determination of Standard Binding Free Energies}, journal = {J Chem Theory Comput}, volume = {13}, year = {2017}, month = {2017 Nov 14}, pages = {5173-5178}, abstract = {

To improve sampling of the configurational entropy change upon protein-ligand binding, we have introduced a new set of coarse variables describing the relative orientation and position of the ligand via a global macromolecular orientational procedure, onto which geometrical restraints are applied. Evaluating the potential of mean force for the different coarse variables, the experimental standard binding free energy for three decapeptides associated with the SH3 domain of the Abl kinase is reproduced quantitatively.

}, issn = {1549-9626}, doi = {10.1021/acs.jctc.7b00791}, author = {Fu, Haohao and Cai, Wensheng and J{\'e}r{\^o}me H{\'e}nin and Roux, Beno{\^\i}t and Chipot, Christophe} } @article {2017|1686, title = {Smoothed biasing forces yield unbiased free energies with the extended-system Adaptive Biasing Force method}, journal = {J. Phys. Chem. B}, volume = {121}, year = {2017}, month = {dec}, pages = {3676{\textendash}3685}, doi = {10.1021/acs.jpcb.6b10055}, author = {Lesage, A. and Leli{\`e}vre, T. and Stoltz, G. and J{\'e}r{\^o}me H{\'e}nin} } @article {2017|2102, title = {Visualization of Biomolecular Structures: State of the Art Revisited: Visualization of Biomolecular Structures}, journal = {Computer Graphics Forum}, volume = {36}, year = {2017}, pages = {178{\textendash}204}, issn = {01677055}, doi = {10.1111/cgf.13072}, url = {http://doi.wiley.com/10.1111/cgf.13072}, author = {Kozlikova, B. and Krone, M. and Falk, M. and Lindow, N. and Marc Baaden and Baum, D. and Viola, I. and Parulek, J. and Hege, H.-C.} } @article {2017|2030, title = {Why Is Research on Amyloid-β Failing to Give New Drugs for Alzheimer{\textquoteright}s Disease?}, journal = {ACS Chem Neurosci}, volume = {8}, year = {2017}, month = {2017 Jul 19}, pages = {1435-1437}, abstract = {

The two hallmarks of Alzheimer\&$\#$39;s disease (AD) are the presence of neurofibrillary tangles (NFT) made of aggregates of the hyperphosphorylated tau protein and of amyloid plaques composed of amyloid-β (Aβ) peptides, primarily Aβ1-40 and Aβ1-42. Targeting the production, aggregation, and toxicity of Aβ with small molecule drugs or antibodies is an active area of AD research due to the general acceptance of the amyloid cascade hypothesis, but thus far all drugs targeting Aβ have failed. From a review of the recent literature and our own experience based on in vitro, in silico, and in vivo studies, we present some reasons to explain this repetitive failure.

}, keywords = {Alzheimer Disease, Amyloid beta-Peptides, Animals, Drug Discovery, Humans, Neuroprotective Agents}, issn = {1948-7193}, doi = {10.1021/acschemneuro.7b00188}, author = {Doig, Andrew J and Del Castillo-Frias, Maria P and Berthoumieu, Olivia and Tarus, Bogdan and Nasica-Labouze, Jessica and Sterpone, Fabio and Phuong Hoang Nguyen and Hooper, Nigel M and Faller, Peter and Philippe Derreumaux} } @article {2016|1746, title = {Evolution of Pentameric Ligand-Gated Ion Channels: Pro-Loop Receptors.}, journal = {Plos One}, volume = {11}, year = {2016}, pages = {e0151934}, abstract = {

Pentameric ligand-gated ion channels (pLGICs) are ubiquitous neurotransmitter receptors in Bilateria, with a small number of known prokaryotic homologues. Here we describe a new inventory and phylogenetic analysis of pLGIC genes across all kingdoms of life. Our main finding is a set of pLGIC genes in unicellular eukaryotes, some of which are metazoan-like Cys-loop receptors, and others devoid of Cys-loop cysteines, like their prokaryotic relatives. A number of such \"Cys-less\" receptors also appears in invertebrate metazoans. Together, those findings draw a new distribution of pLGICs in eukaryotes. A broader distribution of prokaryotic channels also emerges, including a major new archaeal taxon, Thaumarchaeota. More generally, pLGICs now appear nearly ubiquitous in major taxonomic groups except multicellular plants and fungi. However, pLGICs are sparsely present in unicellular taxa, suggesting a high rate of gene loss and a non-essential character, contrasting with their essential role as synaptic receptors of the bilaterian nervous system. Multiple alignments of these highly divergent sequences reveal a small number of conserved residues clustered at the interface between the extracellular and transmembrane domains. Only the \"Cys-loop\" proline is absolutely conserved, suggesting the more fitting name \"Pro loop\" for that motif, and \"Pro-loop receptors\" for the superfamily. The infered molecular phylogeny shows a Cys-loop and a Cys-less clade in eukaryotes, both containing metazoans and unicellular members. This suggests new hypotheses on the evolutionary history of the superfamily, such as a possible origin of the Cys-loop cysteines in an ancient unicellular eukaryote. Deeper phylogenetic relationships remain uncertain, particularly around the split between bacteria, archaea, and eukaryotes.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0151934}, author = {Jaiteh, Mariama and Antoine Taly and J{\'e}r{\^o}me H{\'e}nin} } @article {2016|1672, title = {A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of gamma-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes.}, journal = {J. Biol. Chem}, volume = {291}, year = {2016}, month = {sep}, pages = {20473{\textendash}86}, abstract = {

Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternative targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized, and characterized a chemically active alkylphenol anesthetic (2-((prop-2-yn-1-yloxy)methyl)-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenol, AziPm-click (1)), for affinity-based protein profiling (ABPP) of propofol-binding proteins in their native state within mouse synaptosomes. The ABPP strategy captured approximately 4\% of the synaptosomal proteome, including the unbiased capture of five alpha or beta GABAA receptor subunits. Lack of gamma2 subunit capture was not due to low abundance. Consistent with this, independent molecular dynamics simulations with alchemical free energy perturbation calculations predicted selective propofol binding to interfacial sites, with higher affinities for alpha/beta than gamma-containing interfaces. The simulations indicated hydrogen bonding is a key component leading to propofol-selective binding within GABAA receptor subunit interfaces, with stable hydrogen bonds observed between propofol and alpha/beta cavity residues but not gamma cavity residues. We confirmed this by introducing a hydrogen bond-null propofol analogue as a protecting ligand for targeted-ABPP and observed a lack of GABAA receptor subunit protection. This investigation demonstrates striking interfacial GABAA receptor subunit selectivity in the native milieu, suggesting that asymmetric occupancy of heteropentameric ion channels by alkylphenol-based anesthetics is sufficient to induce modulation of activity.

}, keywords = {anesthesia, anesthetic, click chemistry, GABA receptor, photoaffinity labeling}, doi = {10.1074/jbc.M116.736975}, author = {Woll, Kellie A. and Murlidaran, Sruthi and Pinch, Benika J. and J{\'e}r{\^o}me H{\'e}nin and Wang, Xiaoshi and Salari, Reza and Covarrubias, Manuel and Dailey, William P. and Grace Brannigan and Garcia, Benjamin A. and Roderic G Eckenhoff} } @article {2016|1763, title = {Structure of ring-shaped Aβ42 oligomers determined by conformational selection}, journal = {Sci. Rep.}, volume = {6}, year = {2016}, pages = {21429}, abstract = {

The oligomerization of amyloid beta (Aβ) peptides into soluble non-fibrillar species plays a critical role in the pathogenesis of Alzheimer\&$\#$39;s disease. However, it has been challenging to characterize the tertiary and quaternary structures of Aβ peptides due to their disordered nature and high aggregation propensity. In this work, replica exchange molecular dynamics simulations were used to explore the conformational space of Aβ42 monomer. Among the most populated transient states, we identified a particular conformation which was able to generate ring-shaped pentamers and hexamers, when docked onto itself. The structures of these aggregates were stable during microsecond all-atom MD simulations in explicit solvent. In addition to high resolution models of these oligomers, this study provides support for the conformational selection mechanism of Aβ peptide self-assembly.

}, issn = {2045-2322}, doi = {10.1038/srep21429}, author = {Tran, Linh and Basdevant, Nathalie and Chantal Pr{\'e}vost and Ha-Duong, T{\^a}p} } @article {2016, title = {Visual Analysis of Biomolecular Cavities: State of the Art}, journal = {Comput. Graphics Forum}, volume = {35}, number = {3}, year = {2016}, month = {jun}, pages = {527{\textendash}551}, keywords = {AMBIENT OCCLUSION, ANALYTICAL SHAPE, BINDING-SITE IDENTIFICATION, LIGAND-BINDING, PORE DIMENSIONS, PROTEIN CAVITIES, SURFACE, TIME MOLECULAR VISUALIZATION, TRAVEL DEPTH, WEB SERVER}, url = {https://hal.archives-ouvertes.fr/hal-01400464}, author = {Krone, M. and Kozlikova, B. and Lindow, N. and Marc Baaden and Baum, D. and Parulek, J. and Hege, H.-C. and Viola, I.} } @article {2016|1401, title = {Visualization of Biomolecular Structures: State of the Art Revisited}, journal = {Comput. Graphics Forum}, year = {2016}, month = {nov}, url = {https://hal.archives-ouvertes.fr/hal-01400465}, author = {Kozlikova, B. and Krone, M. and Falk, M. and Lindow, N. and Marc Baaden and Baum, D. and Viola, I. and Parulek, J. and Hege, H.-C.} } @article {2016|1633, title = {Water Determines the Structure and Dynamics of Proteins}, journal = {Chem. Rev.}, volume = {116}, year = {2016}, pages = {7673{\textendash}7697}, author = {M-C. Bellissent-Funel and A. Hassanali and M. Havenith and R. Henchman and P. Pohl and Fabio Sterpone and D. van der Spoel and Y. Xu and A. E. Garcia} } @article {2015|1667, title = {The adaptive biasing force method: everything you always wanted to know but were afraid to ask.}, journal = {J. Phys. Chem. B}, volume = {119}, year = {2015}, month = {jan}, pages = {1129{\textendash}51}, abstract = {

In the host of numerical schemes devised to calculate free energy differences by way of geometric transformations, the adaptive biasing force algorithm has emerged as a promising route to map complex free-energy landscapes. It relies upon the simple concept that as a simulation progresses, a continuously updated biasing force is added to the equations of motion, such that in the long-time limit it yields a Hamiltonian devoid of an average force acting along the transition coordinate of interest. This means that sampling proceeds uniformly on a flat free-energy surface, thus providing reliable free-energy estimates. Much of the appeal of the algorithm to the practitioner is in its physically intuitive underlying ideas and the absence of any requirements for prior knowledge about free-energy landscapes. Since its inception in 2001, the adaptive biasing force scheme has been the subject of considerable attention, from in-depth mathematical analysis of convergence properties to novel developments and extensions. The method has also been successfully applied to many challenging problems in chemistry and biology. In this contribution, the method is presented in a comprehensive, self-contained fashion, discussing with a critical eye its properties, applicability, and inherent limitations, as well as introducing novel extensions. Through free-energy calculations of prototypical molecular systems, many methodological aspects are examined, from stratification strategies to overcoming the so-called hidden barriers in orthogonal space, relevant not only to the adaptive biasing force algorithm but also to other importance-sampling schemes. On the basis of the discussions in this paper, a number of good practices for improving the efficiency and reliability of the computed free-energy differences are proposed.

}, issn = {1520-5207}, doi = {10.1021/jp506633n}, author = {Comer, Jeffrey and Gumbart, James C and J{\'e}r{\^o}me H{\'e}nin and Leli{\`e}vre, Tony and Pohorille, Andrew and Christophe Chipot} } @article {2015|1755, title = {How osmolytes influence hydrophobic polymer conformations: A unified view from experiment and theory.}, journal = {Proc. Natl. Acad. Sci. Usa}, volume = {112}, year = {2015}, pages = {9270{\textendash}5}, abstract = {

It is currently the consensus belief that protective osmolytes such as trimethylamine N-oxide (TMAO) favor protein folding by being excluded from the vicinity of a protein, whereas denaturing osmolytes such as urea lead to protein unfolding by strongly binding to the surface. Despite there being consensus on how TMAO and urea affect proteins as a whole, very little is known as to their effects on the individual mechanisms responsible for protein structure formation, especially hydrophobic association. In the present study, we use single-molecule atomic force microscopy and molecular dynamics simulations to investigate the effects of TMAO and urea on the unfolding of the hydrophobic homopolymer polystyrene. Incorporated with interfacial energy measurements, our results show that TMAO and urea act on polystyrene as a protectant and a denaturant, respectively, while complying with Tanford-Wyman preferential binding theory. We provide a molecular explanation suggesting that TMAO molecules have a greater thermodynamic binding affinity with the collapsed conformation of polystyrene than with the extended conformation, while the reverse is true for urea molecules. Results presented here from both experiment and simulation are in line with earlier predictions on a model Lennard-Jones polymer while also demonstrating the distinction in the mechanism of osmolyte action between protein and hydrophobic polymer. This marks, to our knowledge, the first experimental observation of TMAO-induced hydrophobic collapse in a ternary aqueous system.

}, keywords = {Atomic Force, Computer Simulation, Hydrophobic and Hydrophilic Interactions, Mechanical, Methylamines, Methylamines: chemistry, Microscopy, Molecular Dynamics Simulation, Normal Distribution, Polymers, Polymers: chemistry, Polystyrenes, Polystyrenes: chemistry, Protein Binding, Protein Conformation, Protein Folding, Proteins, Proteins: chemistry, Software, Solvents, Solvents: chemistry, Stress, Thermodynamics, Urea, Urea: chemistry, Water, Water: chemistry}, isbn = {1215421109}, issn = {1091-6490}, doi = {10.1073/pnas.1511780112}, url = {http://www.pnas.org/content/112/30/9270}, author = {Mondal, Jagannath and Halverson, Duncan and Li, Isaac T S and Guillaume Stirnemann and Walker, Gilbert C and Berne, Bruce J} } @article {2015|1975, title = {{A}llosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {112}, number = {9}, year = {2015}, month = {mar}, pages = {2865{\textendash}2870}, author = {Moraga-Cid, G. and Sauguet, L. and Huon, C. and Malherbe, L. and Girard-Blanc, C. and Petres, S. and Murail, S. and Antoine Taly and Marc Baaden and Delarue, M. and Corringer, P. J.} } @article {2015|1664, title = {Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory.}, journal = {J. Membr. Biol.}, volume = {248}, year = {2015}, publisher = {Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527, Athens, Greece, zcournia@bioacademy.gr.}, chapter = {611}, abstract = {

Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.

}, doi = {10.1007/s00232-015-9802-0}, author = {Cournia, Zoe and Allen, Toby W. and Andricioaei, Ioan and Antonny, Bruno and Baum, Daniel and Grace Brannigan and Buchete, Nicolae-Viorel and Deckman, Jason T. and Delemotte, Lucie and Del Val, Coral and Friedman, Ran and Gkeka, Paraskevi and Hege, Hans-Christian and J{\'e}r{\^o}me H{\'e}nin and Kasimova, Marina A. and Kolocouris, Antonios and Michael L Klein and Khalid, Syma and Lemieux, M Joanne and Lindow, Norbert and Roy, Mahua and Selent, Jana and Mounir Tarek and Tofoleanu, Florentina and Vanni, Stefano and Urban, Sinisa and Wales, David J. and Smith, Jeremy C. and Bondar, Ana-Nicoleta} } @article {2015|1668, title = {Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains.}, journal = {J. Phys. Chem. B}, volume = {119}, year = {2015}, month = {jul}, pages = {8939{\textendash}49}, abstract = {

In this work, we address the question of whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologous G domains of different stability: the mesophilic G domain of the elongation factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-1α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time scale, we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favorable for both systems, with the hyperthermophilic protein offering a slightly more favorable environment to host water molecules. We estimate that, under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that, at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that under extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.

}, issn = {1520-5207}, doi = {10.1021/jp507571u}, author = {Rahaman, Obaidur and Kalimeri, Maria and Melchionna, Simone and J{\'e}r{\^o}me H{\'e}nin and Fabio Sterpone} } @conference {2015|1408, title = {Visualization of Biomolecular Structures: State of the Art}, booktitle = {Eurographics Conference on Visualization (EuroVis) - STARs}, year = {2015}, publisher = {The Eurographics Association}, organization = {The Eurographics Association}, author = {Kozlikova, Barbora and Krone, Michael and Lindow, Norbert and Falk, Martin and Marc Baaden and Baum, Daniel and Viola, Ivan and Parulek, Julius and Hege, Hans-Christian}, editor = {R. Borgo and F. Ganovelli and I. Viola} } @article {2014|1792, title = {Allosteric regulation of pentameric ligand-gated ion channels: An emerging mechanistic perspective}, journal = {Channels}, volume = {8}, number = {4}, year = {2014}, pages = {350{\textendash}360}, keywords = {Allosteric Regulation, Animals, chemistry/metabolism, Humans, Ion Channel Gating, Ligand-Gated Ion Channels, metabolism, Models, Molecular, Protein Multimerization, Small Molecule Libraries}, author = {Antoine Taly and J{\'e}r{\^o}me H{\'e}nin and Changeux, Jean-Pierre and Cecchini, Marco} } @article {2014|1669, title = {CHARMM36 united atom chain model for lipids and surfactants.}, journal = {J. Phys. Chem. B}, volume = {118}, number = {2}, year = {2014}, month = {jan}, pages = {547{\textendash}556}, publisher = {, Maryland 20742, United States.}, abstract = {Molecular simulations of lipids and surfactants require accurate parameters to reproduce and predict experimental properties. Previously, a united atom (UA) chain model was developed for the CHARMM27/27r lipids (H{\'e}nin, J., et al. J. Phys. Chem. B. 2008, 112, 7008-7015) but suffers from the flaw that bilayer simulations using the model require an imposed surface area ensemble, which limits its use to pure bilayer systems. A UA-chain model has been developed based on the CHARMM36 (C36) all-atom lipid parameters, termed C36-UA, and agreed well with bulk, lipid membrane, and micelle formation of a surfactant. Molecular dynamics (MD) simulations of alkanes (heptane and pentadecane) were used to test the validity of C36-UA on density, heat of vaporization, and liquid self-diffusion constants. Then, simulations using C36-UA resulted in accurate properties (surface area per lipid, X-ray and neutron form factors, and chain order parameters) of various saturated- and unsaturated-chain bilayers. When mixed with the all-atom cholesterol model and tested with a series of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/cholesterol mixtures, the C36-UA model performed well. Simulations of self-assembly of a surfactant (dodecylphosphocholine, DPC) using C36-UA suggest an aggregation number of 53 {\textpm} 11 DPC molecules at 0.45 M of DPC, which agrees well with experimental estimates. Therefore, the C36-UA force field offers a useful alternative to the all-atom C36 lipid force field by requiring less computational cost while still maintaining the same level of accuracy, which may prove useful for large systems with proteins.}, keywords = {analogs /\&/ derivatives/chemistry, chemistry, Cholesterol, Dimyristoylphosphatidylcholine, Lipid Bilayers, Lipids, Micelles, Molecular Dynamics Simulation, Phosphorylcholine, Surface-Active Agents}, doi = {10.1021/jp410344g}, author = {Lee, Sarah and Tran, Alan and Allsopp, Matthew and Lim, Joseph B. and J{\'e}r{\^o}me H{\'e}nin and Klauda, Jeffery B.} } @inbook {2014|1720, title = {Foundations of Biomolecular Simulations: A Critical Introduction to Homology Modeling, Molecular Dynamics Simulations, and Free Energy Calculations of Membrane Proteins}, booktitle = {Membrane Proteins Production for Structural Analysis}, year = {2014}, pages = {347{\textendash}392}, publisher = {Springer New York}, organization = {Springer New York}, author = {J{\'e}r{\^o}me H{\'e}nin and Marc Baaden and Antoine Taly} } @article {2014|1411, title = {{I}nnovative interactive flexible docking method for multi-scale reconstruction elucidates dystrophin molecular assembly}, journal = {Faraday Discuss.}, volume = {169}, year = {2014}, note = {[DOI:\href{http://dx.doi.org/10.1039/c3fd00134b}{10.1039/c3fd00134b}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25340652}{25340652}]}, pages = {45{\textendash}62}, author = {Molza, A. E and Nicolas F{\'e}rey and Czjzek, M and Le Rumeur, E and Hubert, J. F and Tek, A and Laurent, B and Marc Baaden and Delalande, O.} } @article {2014|1717, title = {Lipid concentration and molar ratio boundaries for the use of isotropic bicelles.}, journal = {Langmuir}, volume = {30}, number = {21}, year = {2014}, month = {jun}, pages = {6162{\textendash}6170}, publisher = {Department of Chemistry, Universit{\'e} du Qu{\'e}bec {\`a} Montr{\'e}al and Centre Qu{\'e}b{\'e}cois sur les Mat{\'e}riaux Fonctionnels , P.O. Box 8888, Downtown Station, Montreal, Canada H3C 3P8.}, abstract = {Bicelles are model membranes generally made of long-chain dimyristoylphosphatidylcholine (DMPC) and short-chain dihexanoyl-PC (DHPC). They are extensively used in the study of membrane interactions and structure determination of membrane-associated peptides, since their composition and morphology mimic the widespread PC-rich natural eukaryotic membranes. At low DMPC/DHPC (q) molar ratios, fast-tumbling bicelles are formed in which the DMPC bilayer is stabilized by DHPC molecules in the high-curvature rim region. Experimental constraints imposed by techniques such as circular dichroism, dynamic light scattering, or microscopy may require the use of bicelles at high dilutions. Studies have shown that such conditions induce the formation of small aggregates and alter the lipid-to-detergent ratio of the bicelle assemblies. The objectives of this work were to determine the exact composition of those DMPC/DHPC isotropic bicelles and study the lipid miscibility. This was done using (31)P nuclear magnetic resonance (NMR) and exploring a wide range of lipid concentrations (2-400 mM) and q ratios (0.15-2). Our data demonstrate how dilution modifies the actual DMPC/DHPC molar ratio in the bicelles. Care must be taken for samples with a total lipid concentration <=250 mM and especially at q \~{} 1.5-2, since moderate dilutions could lead to the formation of large and slow-tumbling lipid structures that could hinder the use of solution NMR methods, circular dichroism or dynamic light scattering studies. Our results, supported by infrared spectroscopy and molecular dynamics simulations, also show that phospholipids in bicelles are largely segregated only when q > 1. Boundaries are presented within which control of the bicelles{\textquoteright} q ratio is possible. This work, thus, intends to guide the choice of q ratio and total phospholipid concentration when using isotropic bicelles.}, keywords = {chemistry, Circular Dichroism, Detergents, Dimyristoylphosphatidylcholine, Fourier Transform Infrared, Light, Lipid Bilayers, Magnetic Resonance Spectroscopy, Materials Testing, Micelles, Molecular Dynamics Simulation, Phospholipid Ethers, Phospholipids, Radiation, Scattering, Solutions, Spectroscopy, Temperature}, doi = {10.1021/la5004353}, author = {Beaugrand, Ma\"{\i}wenn and Arnold, Alexandre A. and J{\'e}r{\^o}me H{\'e}nin and Warschawski, Dror E. and Williamson, Philip T F. and Marcotte, Isabelle} } @article {2014|1413, title = {{M}olecular simulations and visualization: introduction and overview}, journal = {Faraday Discuss.}, volume = {169}, year = {2014}, note = {[DOI:\href{http://dx.doi.org/10.1039/c4fd90024c}{10.1039/c4fd90024c}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25285906}{25285906}]}, pages = {9{\textendash}22}, author = {Hirst, J. D. and Glowacki, D. R. and Marc Baaden} } @conference {2014|1760, title = {Optogating a powerful approach to control an ion-channel gate}, booktitle = {PURINERGIC SIGNALLING}, volume = {10}, number = {4}, year = {2014}, pages = {762{\textendash}762}, publisher = {SPRINGER VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS}, organization = {SPRINGER VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS}, author = {Lemoine, Damien and Habermacher, Chlo{\'e} and Martz, Adeline and M{\'e}ry, Pierre-Fran\c cois and Bouquier, Nathalie and Diverchy, Fanny and Antoine Taly and Rassendren, Fran\c cois and Specht, Alexandre and Grutter, Thomas} } @article {2014|1598, title = {A predicted binding site for cholesterol on the GABAA receptor.}, journal = {Biophys. J.}, volume = {106}, number = {9}, year = {2014}, month = {may}, pages = {1938{\textendash}1949}, publisher = {Department of Physics, Rutgers University-Camden, Camden, New Jersey; Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, New Jersey. Electronic address: Grace.Brannigan@rutgers.edu.}, abstract = {Modulation of the GABA type A receptor (GABAAR) function by cholesterol and other steroids is documented at the functional level, yet its structural basis is largely unknown. Current data on structurally related modulators suggest that cholesterol binds to subunit interfaces between transmembrane domains of the GABAAR. We construct homology models of a human GABAAR based on the structure of the glutamate-gated chloride channel GluCl of Caenorhabditis elegans. The models show the possibility of previously unreported disulfide bridges linking the M1 and M3 transmembrane helices in the α and γ subunits. We discuss the biological relevance of such disulfide bridges. Using our models, we investigate cholesterol binding to intersubunit cavities of the GABAAR transmembrane domain. We find that very similar binding modes are predicted independently by three approaches: analogy with ivermectin in the GluCl crystal structure, automated docking by AutoDock, and spontaneous rebinding events in unbiased molecular dynamics simulations. Taken together, the models and atomistic simulations suggest a somewhat flexible binding mode, with several possible orientations. Finally, we explore the possibility that cholesterol promotes pore opening through a wedge mechanism.}, keywords = {Amino Acid, Binding Sites, Caenorhabditis elegans Proteins, chemistry, chemistry/metabolism, Chloride Channels, Cholesterol, GABA-A, Humans, Hydrogen Bonding, Ivermectin, metabolism, Molecular Docking Simulation, Molecular Dynamics Simulation, Porosity, Protein Binding, Protein Conformation, Receptors, Sequence Homology, Substrate Specificity}, doi = {10.1016/j.bpj.2014.03.024}, author = {J{\'e}r{\^o}me H{\'e}nin and Salari, Reza and Murlidaran, Sruthi and Grace Brannigan} } @article {2014|1645, title = {Type VI secretion and bacteriophage tail tubes share a common assembly pathway.}, journal = {Embo Rep.}, volume = {15}, year = {2014}, month = {mar}, pages = {315{\textendash}21}, abstract = {

The Type VI secretion system (T6SS) is a widespread macromolecular structure that delivers protein effectors to both eukaryotic and prokaryotic recipient cells. The current model describes the T6SS as an inverted phage tail composed of a sheath-like structure wrapped around a tube assembled by stacked Hcp hexamers. Although recent progress has been made to understand T6SS sheath assembly and dynamics, there is no evidence that Hcp forms tubes in vivo. Here we show that Hcp interacts with TssB, a component of the T6SS sheath. Using a cysteine substitution approach, we demonstrate that Hcp hexamers assemble tubes in an ordered manner with a head-to-tail stacking that are used as a scaffold for polymerization of the TssB/C sheath-like structure. Finally, we show that VgrG but not TssB/C controls the proper assembly of the Hcp tubular structure. These results highlight the conservation in the assembly mechanisms between the T6SS and the bacteriophage tail tube/sheath.

}, keywords = {Amino Acid Sequence, Bacterial Secretion Systems, Escherichia coli, Escherichia coli Proteins, Molecular Sequence Data, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Virulence Factors}, issn = {1469-3178}, doi = {10.1002/embr.201337936}, author = {Brunet, Yannick R and J{\'e}r{\^o}me H{\'e}nin and Celia, Herv{\'e} and Cascales, Eric} } @article {2013|1797, title = {Biomolecular hydration dynamics: a jump model perspective}, journal = {Chem. Soc. Rev.}, volume = {42}, number = {13}, year = {2013}, pages = {5672{\textendash}5683}, author = {Fogarty, Aoife C. and Elise Dubou{\'e}-Dijon and Sterpone, Fabio and Hynes, James T. and Laage, Damien} } @article {2013|1747, title = {A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia}, journal = {Plos One}, volume = {8}, number = {1}, year = {2013}, publisher = {Public Library of Science}, author = {Ammar, A Ben and Soltanzadeh, Payam and Bauch{\'e}, St{\'e}phanie and Richard, Pascale and Goillot, Evelyne and Herbst, Ruth and Gaudon, Karen and Huz{\'e}, Caroline and Schaeffer, Laurent and Yamanashi, Yuji and others} } @article {2013|1973, title = {{O}ptical control of an ion channel gate}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {110}, number = {51}, year = {2013}, month = {dec}, pages = {20813{\textendash}20818}, author = {Lemoine, D. and Habermacher, C. and Martz, A. and Mery, P. F. and Bouquier, N. and Diverchy, F. and Antoine Taly and Rassendren, F. and Specht, A. and Grutter, T.} } @article {2013|1936, title = {Using collective variables to drive molecular dynamics simulations}, journal = {Mol. Phys.}, volume = {111}, number = {22-23}, year = {2013}, pages = {3345{\textendash}3362}, doi = {10.1080/00268976.2013.813594}, author = {Giacomo Fiorin and Michael L Klein and J{\'e}r{\^o}me H{\'e}nin} } @inbook {2012|1575, title = {Advances in Human-Protein Interaction - Interactive And Immersive Molecular Simulations}, year = {2012}, publisher = {Intech, Croatia}, organization = {Intech, Croatia}, chapter = {Protein Interaction / Book 2}, author = {A. Tek and B. Laurent and M. Piuzzi and Z. Lu and Marc Baaden and O. Delalande and Matthieu Chavent and Nicolas F{\'e}rey and C. Martin and L. Piccinali and B. Katz and P. Bourdot and Ludovic Autin}, editor = {W. Cai and H. Hong} } @article {2012|1382, title = {Bient{\^o}t dans votre amphith{\'e}{\^a}tre, la chimie fera son cin{\'e}ma. De la bonne utilisation des ressources informatiques pour l{\textquoteright}enseignement : visualisation mol{\'e}culaire, illustration de processus chimiques et de mod{\`e}les physiques}, journal = {Actualit{\'e} Chimique}, volume = {363}, year = {2012}, author = {Matthieu Chavent and Marc Baaden and E. H{\'e}non and S. Antonczak} } @article {2012|1960, title = {General Anesthetics Predicted to Block the {GLIC} Pore with Micromolar Affinity}, journal = {Plos Comput. Biol.}, volume = {8}, number = {5}, year = {2012}, pages = {e1002532}, publisher = {Public Library of Science}, abstract = {

Author Summary

Although general anesthesia is performed every day on thousands of people, its detailed microscopic mechanisms are not known. What is known is that general anesthetic drugs modulate the activity of ion channels in the central nervous system. These channels are proteins that open in response to binding of neurotransmitter molecules, creating an electric current through the cell membrane and thus propagating nerve impulses between cells. One possible mechanism for ion channel inhibition by anesthetics is that the drugs bind inside the pore of the channels, blocking ion current. Here we investigate such a pore block mechanism by computing the strength of the drugs{\textquoteright} interaction with the pore {\textendash} and hence the likelihood of binding, in the case of GLIC, a bacterial channel protein. The results, obtained from numerical simulations of atomic models of GLIC, indicate that the anesthetics isoflurane and propofol have a tendency to bind in the pore that is strong enough to explain blocking of the channel, even at low concentration of the drugs.

}, doi = {10.1371/journal.pcbi.1002532}, url = {http://dx.doi.org/10.1371\%2Fjournal.pcbi.1002532}, author = {LeBard, David N. and J{\'e}r{\^o}me H{\'e}nin and Roderic G Eckenhoff and Michael L Klein and Brannigan, Grace} } @article {2012|1506, title = {A novel Locally Closed Conformation of a Bacterial Pentameric Proton-gated Ion Channel}, journal = {Nature Structural \& Molecular Biology}, year = {2012}, month = {apr}, author = {M. Prevost and L. Sauguet and H. Nury and C. Van Renterghem and C. Huon and F. Poitevin and Marc Baaden and M. Delarue and P.-J. Corringer} } @article {2012|1753, title = {Rate limit of protein elastic response is tether dependent}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {109}, year = {2012}, pages = {14416{\textendash}14421}, abstract = {

The elastic restoring force of tissues must be able to operate over the very wide range of loading rates experienced by living organisms. It is surprising that even the fastest events involving animal muscle tissues do not surpass a few hundred hertz. We propose that this limit is set in part by the elastic dynamics of tethered proteins extending and relaxing under a changing load. Here we study the elastic dynamics of tethered proteins using a fast force spectrometer with sub-millisecond time resolution, combined with Brownian and Molecular Dynamics simulations. We show that the act of tethering a polypeptide to an object, an inseparable part of protein elasticity in vivo and in experimental setups, greatly reduces the attempt frequency with which the protein samples its free energy. Indeed, our data shows that a tethered polypeptide can traverse its free-energy landscape with a surprisingly low effective diffusion coefficient D(eff) \~{} 1,200 nm(2)/s. By contrast, our Molecular Dynamics simulations show that diffusion of an isolated protein under force occurs at D(eff) \~{} 10(8) nm(2)/s. This discrepancy is attributed to the drag force caused by the tethering object. From the physiological time scales of tissue elasticity, we calculate that tethered elastic proteins equilibrate in vivo with D(eff) \~{} 10(4)-10(6) nm(2)/s which is two to four orders magnitude smaller than the values measured for untethered proteins in bulk.

}, issn = {0027-8424}, author = {Berkovich, R. and Hermans, R. I. and Popa, I. and Guillaume Stirnemann and Garcia-Manyes, S. and Berne, B. J. and Fernandez, J. M.} } @article {2012|1813, title = {Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders}, journal = {Hum. Mol. Genet.}, volume = {21}, number = {26}, year = {2012}, month = {dec}, pages = {5417{\textendash}5428}, doi = {10.1093/hmg/dds377}, author = {Katell Peoc{\textquoteright}h and Etienne Levavasseur and Emilien Delmont and Alfonso De Simone Isabelle Laffont-Proust and Nicolas Privat and Y Chebaro and C{\'e}line Chapuis Pierre Bedoucha and Jean-Philippe Brandel and Annie Laquerriere and Jean-Louis Kemeny Jean-Jacques Hauw and Michel Borg and Human Rezaei and Philippe Derreumaux Jean-Louis Laplanche and St{\'e}phane Ha{\"\i}k} } @article {2012|1684, title = {Water jump reorientation and ultrafast vibrational spectroscopy}, journal = {J. Photochem. Photobiol. A}, volume = {234}, year = {2012}, pages = {75{\textendash}82}, abstract = {

The reorganization of water{\textquoteright}s hydrogen-bond (HB) network by breaking and making HBs lies at the heart of many of the pure liquid{\textquoteright}s special features and many aqueous media phenomena, including chemical reactions, ion transport and protein activity. An essential role in this reorganization is played by water molecule reorientation, long described by very small angular displacement Debye rotational diffusion. A markedly contrasting picture has been recently proposed, based on simulation and analytic modeling: a sudden, large amplitude jump mechanism, in which the reorienting water molecule rapidly exchanges HB partners in an activated process which has all the hallmarks of a chemical reaction. In this contribution, we offer a brief review of the jump mechanism together with a discussion of its application to, and probing by, modern ultrafast infrared spectroscopy experiments. Special emphasis is given to the direct characterization of the jumps via pioneering two-dimensional infrared spectroscopic measurements. ?? 2012 Elsevier B.V. All rights reserved.

}, keywords = {Hydrogen-bond dynamics, Pump-probe infrared spectroscopy, Two-dimensional infrared spectroscopy, Water dynamics}, issn = {10106030}, author = {Laage, Damien and Guillaume Stirnemann and Hynes, James T.} } @article {2012, title = {Water Jump Reorientation: From Theoretical Prediction to Experimental Observation}, journal = {Acc. Chem. Res.}, volume = {45}, number = {1}, year = {2012}, pages = {53{\textendash}62}, doi = {10.1021/ar200075u}, author = {Laage, Damien and Guillaume Stirnemann and Sterpone, Fabio and Hynes, James T.} } @article {2011|1665, title = {Community-wide assessment of protein-interface modeling suggests improvements to design methodology.}, journal = {J. Mol. Biol.}, volume = {414}, year = {2011}, month = {nov}, pages = {289{\textendash}302}, abstract = {

The CAPRI (Critical Assessment of Predicted Interactions) and CASP (Critical Assessment of protein Structure Prediction) experiments have demonstrated the power of community-wide tests of methodology in assessing the current state of the art and spurring progress in the very challenging areas of protein docking and structure prediction. We sought to bring the power of community-wide experiments to bear on a very challenging protein design problem that provides a complementary but equally fundamental test of current understanding of protein-binding thermodynamics. We have generated a number of designed protein-protein interfaces with very favorable computed binding energies but which do not appear to be formed in experiments, suggesting that there may be important physical chemistry missing in the energy calculations. A total of 28 research groups took up the challenge of determining what is missing: we provided structures of 87 designed complexes and 120 naturally occurring complexes and asked participants to identify energetic contributions and/or structural features that distinguish between the two sets. The community found that electrostatics and solvation terms partially distinguish the designs from the natural complexes, largely due to the nonpolar character of the designed interactions. Beyond this polarity difference, the community found that the designed binding surfaces were, on average, structurally less embedded in the designed monomers, suggesting that backbone conformational rigidity at the designed surface is important for realization of the designed function. These results can be used to improve computational design strategies, but there is still much to be learned; for example, one designed complex, which does form in experiments, was classified by all metrics as a nonbinder.

}, keywords = {Binding Sites, Models, Molecular, Protein Binding, Proteins}, issn = {1089-8638}, doi = {10.1016/j.jmb.2011.09.031}, author = {Fleishman, Sarel J and Whitehead, Timothy A and Strauch, Eva-Maria and Corn, Jacob E and Qin, Sanbo and Zhou, Huan-Xiang and Mitchell, Julie C and Demerdash, Omar N A and Takeda-Shitaka, Mayuko and Terashi, Genki and Moal, Iain H and Li, Xiaofan and Bates, Paul A and Martin Zacharias and Park, Hahnbeom and Ko, Jun-su and Lee, Hasup and Seok, Chaok and Bourquard, Thomas and Bernauer, Julie and Poupon, Anne and Az{\'e}, J{\'e}r{\^o}me and Soner, Seren and Ovali, Sefik Kerem and Ozbek, Pemra and Tal, Nir Ben and Haliloglu, T{\"u}rkan and Hwang, Howook and Vreven, Thom and Pierce, Brian G and Weng, Zhiping and P{\'e}rez-Cano, Laura and Pons, Carles and Fern{\'a}ndez-Recio, Juan and Jiang, Fan and Yang, Feng and Gong, Xinqi and Cao, Libin and Xu, Xianjin and Liu, Bin and Wang, Panwen and Li, Chunhua and Wang, Cunxin and Charles H. Robert and Guharoy, Mainak and Liu, Shiyong and Huang, Yangyu and Li, Lin and Guo, Dachuan and Chen, Ying and Xiao, Yi and London, Nir and Itzhaki, Zohar and Schueler-Furman, Ora and Inbar, Yuval and Potapov, Vladimir and Cohen, Mati and Schreiber, Gideon and Tsuchiya, Yuko and Kanamori, Eiji and Standley, Daron M and Nakamura, Haruki and Kinoshita, Kengo and Driggers, Camden M and Hall, Robert G and Morgan, Jessica L and Hsu, Victor L and Zhan, Jian and Yang, Yuedong and Zhou, Yaoqi and Kastritis, Panagiotis L and Bonvin, Alexandre M J J and Zhang, Weiyi and Camacho, Carlos J and Kilambi, Krishna P and Sircar, Aroop and Gray, Jeffrey J and Ohue, Masahito and Uchikoga, Nobuyuki and Matsuzaki, Yuri and Ishida, Takashi and Akiyama, Yutaka and Khashan, Raed and Bush, Stephen and Fouches, Denis and Tropsha, Alexander and Esquivel-Rodr{\'\i}guez, Juan and Kihara, Daisuke and Stranges, P Benjamin and Jacak, Ron and Kuhlman, Brian and Huang, Sheng-You and Zou, Xiaoqin and Wodak, Shoshana J and Janin, Jo{\"e}l and Baker, David} } @article {2011|1738, title = {Non-monotonic dependence of water reorientation dynamics on surface hydrophilicity: competing effects of the hydration structure and hydrogen-bond strength}, journal = {Phys. Chem. Chem. Phys.}, volume = {13}, year = {2011}, pages = {19911}, abstract = {

The reorientation dynamics of interfacial water molecules was recently shown to change non-monotonically next to surfaces of increasing hydrophilicity, with slower dynamics next to strongly hydrophobic (apolar) and very hydrophilic surfaces, and faster dynamics next to surfaces of intermediate hydrophilicities. Through a combination of molecular dynamics simulations and analytic modeling, we provide a molecular interpretation of this behavior. We show that this non-monotonic dependence arises from two competing effects induced by the increasing surface hydrophilicity: first a change in the hydration structure with an enhanced population of water OH bonds pointing toward the surface and second a strengthening of the water-surface interaction energy. The extended jump model, including the effects due to transition-state excluded volume and transition-state hydrogen-bond strength, provides a quasi-quantitative description of the non-monotonic changes in the water reorientation dynamics with surface hydrophilicity.

}, issn = {1463-9076}, author = {Guillaume Stirnemann and Castrillon, Santiago Romero-Vargas and Hynes, James T. and Rossky, Peter J. and Debenedetti, Pablo G. and Laage, Damien} } @article {2011|1383, title = {Reorientation and Allied Dynamics in Water and Aqueous Solutions}, journal = {Annu. Rev. Phys. Chem.}, volume = {62}, year = {2011}, pages = {395{\textendash}416}, abstract = {

The reorientation of a water molecule is important for a host of phenomena, ranging over?in an only partial listing?the key dynamic hydrogen-bond network restructuring of water itself, aqueous solution chemical reaction mechanisms and rates, ion transport in aqueous solution and membranes, protein folding, and enzymatic activity. This review focuses on water reorientation and related dynamics in pure water, and for aqueous solutes with hydrophobic, hydrophilic, and amphiphilic character, ranging from tetramethylurea to halide ions and amino acids. Attention is given to the application of theory, simulation, and experiment in the probing of these dynamics, in usefully describing them, and in assessing the description. Special emphasis is placed on a novel sudden, large-amplitude jump mechanism for water reorientation, which contrasts with the commonly assumed Debye rotational diffusion mechanism, characterized by small-amplitude angular motion. Some open questions and directions for further research are also discussed. Expected final online publication date for the Annual Review of Physical Chemistry Volume 62 is March 31, 2011. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

}, isbn = {0066-426X 1545-1593}, issn = {0066-426X}, doi = {doi: 10.1146/annurev.physchem.012809.103503}, url = {http://www.annualreviews.org/doi/abs/10.1146/annurev.physchem.012809.103503$\backslash$nhttp://www.annualreviews.org.login.ezproxy.lib.purdue.edu/doi/pdf/10.1146/annurev.physchem.012809.103503}, author = {Laage, Damien and Guillaume Stirnemann and Fabio Sterpone and Rey, Rossend and Hynes, James T.} } @article {2011|1739, title = {Water reorientation dynamics in the first hydration shells of F- and I-}, journal = {Phys. Chem. Chem. Phys.}, volume = {13}, year = {2011}, pages = {19895}, abstract = {

Molecular dynamics and analytic theory results are presented for the reorientation dynamics of first hydration shell water molecules around fluoride and iodide anions. These ions represent the extremes of the (normal) halide series in terms of their size and conventional structure-making and -breaking categorizations. The simulated reorientation times are consistent with NMR and ultrafast IR experimental results. They are also in good agreement with the theoretical predictions of the analytic Extended Jump Model. Analysis through this model shows that while sudden, large amplitude jumps (in which the reorienting water exchanges hydrogen-bond partners) are the dominant reorientation pathway for the I(-) case, they are comparatively less important for the F(-) case. In particular, the diffusive reorientation of an intact F(-)...H(2)O hydrogen-bonded pair is found to be most important for the reorientation time, a feature related to the greater hydrogen-bond strength for the F(-)...H(2)O pair. The dominance of this effect for e.g. multiply charged ions is suggested.

}, issn = {1463-9076}, author = {Boisson, Jean and Guillaume Stirnemann and Laage, Damien and Hynes, James T.} } @article {2010|1865, title = {An atomistic model for simulations of the general anesthetic isoflurane}, journal = {J. Phys. Chem. B}, volume = {114}, number = {1}, year = {2010}, pages = {604{\textendash}612}, publisher = {Laboratoire d{\textquoteright}Ing{\'e}nierie des Syst{\`e}mes Macromol{\'e}culaires, CNRS, Marseille, France. jhenin@ifr88.cnrs-mrs.fr}, abstract = {An atomistic model of isoflurane is constructed and calibrated to describe its conformational preferences and intermolecular interactions. The model, which is compatible with the CHARMM force field for biomolecules, is based on target quantities including bulk liquid properties, molecular conformations, and local interactions with isolated water molecules. Reference data is obtained from tabulated thermodynamic properties and high-resolution structural information from gas-phase electron diffraction, as well as DFT calculations at the B3LYP level. The model is tested against experimentally known solvation properties in water and oil, and shows quantitative agreement. In particular, isoflurane is faithfully described as lipophilic, yet nonhydrophobic, a combination of properties critical to its pharmacological activity. Intermolecular interactions of the model are further probed through simulations of the binding of isoflurane to a binding site in horse spleen apoferritin (HSAF). The observed binding mode compares well with crystallographic data, and the calculated binding affinities are compatible with experimental results, although both computational and experimental measurements are challenging and provide results with limited precision. The model is expected to be useful for detailed simulations of the elementary molecular processes associated with anesthesia. Full parameters are provided as Supporting Information.}, doi = {10.1021/jp9088035}, author = {J{\'e}r{\^o}me H{\'e}nin and Grace Brannigan and William P Dailey and Roderic G Eckenhoff and Michael L Klein} } @article {2010|1510, title = {{D}{N}{A} structures from phosphate chemical shifts}, journal = {Nucleic Acids Res.}, volume = {38}, year = {2010}, month = {jan}, pages = {e18}, author = {Abi-Ghanem, J. and Heddi, B. and Foloppe, N. and Hartmann, B.} } @article {2010|1851, title = {Exploring Multidimensional Free Energy Landscapes Using Time-Dependent Biases on Collective Variables}, journal = {J. Chem. Theory Comput.}, volume = {6}, number = {1}, year = {2010}, pages = {35{\textendash}47}, author = {J{\'e}r{\^o}me H{\'e}nin and Giacomo Fiorin and Christophe Chipot and Michael L Klein} } @article {2010|1524, title = {{H}ow cations can assist {D}{N}ase {I} in {D}{N}{A} binding and hydrolysis}, journal = {Plos Comput. Biol.}, volume = {6}, year = {2010}, month = {nov}, pages = {e1001000}, author = {M. Gueroult and D. Picot and J. Abi-Ghanem and B. Hartmann and Marc Baaden} } @article {2010|1511, title = {{I}ntrinsic flexibility of {B}-{D}{N}{A}: the experimental {T}{R}{X} scale}, journal = {Nucleic Acids Res.}, volume = {38}, year = {2010}, month = {jan}, pages = {1034{\textendash}1047}, author = {Heddi, B. and Oguey, C. and Lavelle, C. and Foloppe, N. and Hartmann, B.} } @article {2010|1516, title = {{M}ulti-resolution approach for interactively locating functionally linked ion binding sites by steering small molecules into electrostatic potential maps using a haptic device}, journal = {Pac. Symp. Biocomput.}, year = {2010}, pages = {205{\textendash}215}, author = {Delalande, O. and Nicolas F{\'e}rey and Laurent, B. and Gueroult, M. and Hartmann, B. and Marc Baaden} } @article {2010|1971, title = {Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain.}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {107}, number = {32}, year = {2010}, pages = {14122{\textendash}14127}, abstract = {An extensive search for isoflurane binding sites in the nicotinic acetylcholine receptor (nAChR) and the proton gated ion channel from Gloebacter violaceus (GLIC) has been carried out based on molecular dynamics (MD) simulations in fully hydrated lipid membrane environments. Isoflurane introduced into the aqueous phase readily partitions into the lipid membrane and the membrane-bound protein. Specifically, isoflurane binds persistently to three classes of sites in the nAChR transmembrane domain: (i) An isoflurane dimer occludes the pore, contacting residues identified by previous mutagenesis studies; analogous behavior is observed in GLIC. (ii) Several nAChR subunit interfaces are also occupied, in a site suggested by photoaffinity labeling and thought to positively modulate the receptor; these sites are not occupied in GLIC. (iii) Isoflurane binds to the subunit centers of both nAChR alpha chains and one of the GLIC chains, in a site that has had little experimental targeting. Interpreted in the context of existing structural and physiological data, the present MD results support a multisite model for the mechanism of receptor-channel modulation by anesthetics.}, doi = {10.1073/pnas.1008534107}, author = {Grace Brannigan and David N LeBard and J{\'e}r{\^o}me H{\'e}nin and Roderic G Eckenhoff and Michael L Klein} } @article {2010|1456, title = {{S}equence-dependent {D}{N}{A} flexibility mediates {D}{N}ase {I} cleavage}, journal = {J. Mol. Biol.}, volume = {395}, year = {2010}, month = {jan}, pages = {123{\textendash}133}, author = {Heddi, B. and Abi-Ghanem, J. and Lavigne, M. and Hartmann, B.} } @article {2010|1789, title = {Single-spanning transmembrane domains in cell growth and cell-cell interactions: More than meets the eye?}, journal = {Cell Adh. Migr.}, volume = {4}, number = {2}, year = {2010}, month = {apr}, pages = {313{\textendash}324}, abstract = {

As a whole, integral membrane proteins represent about one third of sequenced genomes, and more than 50\% of currently available drugs target membrane proteins, often cell surface receptors. Some membrane protein classes, with a defined number of transmembrane (TM) helices, are receiving much attention because of their great functional and pharmacological importance, such as G protein-coupled receptors possessing 7 TM segments. Although they represent roughly half of all membrane proteins, bitopic proteins (with only 1 TM helix) have so far been less well characterized. Though they include many essential families of receptors, such as adhesion molecules and receptor tyrosine kinases, many of which are excellent targets for biopharmaceuticals (peptides, antibodies, et al.). A growing body of evidence suggests a major role for interactions between TM domains of these receptors in signaling, through homo and heteromeric associations, conformational changes, assembly of signaling platforms, etc. Significantly, mutations within single domains are frequent in human disease, such as cancer or developmental disorders. This review attempts to give an overview of current knowledge about these interactions, from structural data to therapeutic perspectives, focusing on bitopic proteins involved in cell signaling.

}, keywords = {Animals, Biological, Humans, Membrane Proteins, Models, Protein Structure, Secondary, Signal Transduction, Tertiary}, issn = {1933-6926}, doi = {10.4161/cam.4.2.12430}, author = {Pierre Hubert and Paul Sawma and Jean-Pierre Duneau and Jonathan Khao and J{\'e}r{\^o}me H{\'e}nin and Dominique Bagnard and James Sturgis} } @article {2010|1692, title = {Water hydrogen bond dynamics in aqueous solutions of amphiphiles}, journal = {J. Phys. Chem. B}, volume = {114}, year = {2010}, pages = {3052{\textendash}3059}, abstract = {

The hydrogen bond dynamics of water in a series of amphiphilic solute solutions are investigated through simulations and analytic modeling with an emphasis on the interpretation of experimentally accessible two-dimensional infrared (2D IR) photon echo spectra. We evidence that for most solutes the major effect in the hydration dynamics comes from the hydrophilic groups. These groups can retard the water dynamics much more significantly than can hydrophobic groups by forming strong hydrogen bonds with water. By contrast, hydrophobic groups are shown to have a very moderate effect on water hydrogen bond breaking kinetics. We also present the first calculation of the 2D IR spectra for these solutions. While 2D IR spectroscopy is a powerful technique to probe water hydrogen bond network fluctuations, interpretations of aqueous solution spectra remain ambiguous. We show that a complementary approach through simulations and calculation of the spectra lifts the ambiguity and provides a clear connection between the simulated molecular picture and the experimental spectroscopy data. For amphiphilic solute solutions, we show that, in contrast with techniques such as NMR or ultrafast anisotropy, 2D IR spectroscopy can discriminate between waters next to the solutes hydrophobic and hydrophilic groups. We also evidence that the water dynamics slowdown due to the hydrophilic groups is dramatically enhanced in the 2D IR spectral relaxation, because these groups can induce a slow chemical exchange with the bulk, even when recognized exchange signatures are absent. Implications for the understanding of water around chemically heterogeneous systems such as protein surfaces and for the interpretation of 2D IR spectra in these cases are discussed.

}, issn = {15206106}, author = {Guillaume Stirnemann and Hynes, James T. and Laage, Damien} } @article {2010|1832, title = {Water hydrogen-bond dynamics around amino acids: the key role of hydrophilic hydrogen-bond acceptor groups}, journal = {J. Phys. Chem. B}, volume = {114}, number = {5}, year = {2010}, pages = {2083{\textendash}9}, abstract = {

Water hydrogen-bond (HB) dynamics around amino acids in dilute aqueous solution is investigated through molecular dynamics simulations and analytic modeling. We especially highlight the critical role played by hydrophilic HB acceptors: the strength of the HB formed with water has a pronounced effect on the HB dynamics, in accord with several experimental observations. In contrast, we evidence that hydrophilic HB donors induce a moderate slowdown in the water HB exchange dynamics due to an excluded volume effect, similar to that of hydrophobic groups. We present an analytic model which rationalizes the effect of all examined amino acid sites on the HB dynamics and whose predictions are in excellent agreement with the numerical simulations. This model provides the acceleration or retardation in the HB exchange time with respect to the bulk through the combination of the solute excluded volume factor with the solute-water HB strength factor, both referring to the HB exchange transition state.

}, author = {Sterpone, Fabio and Guillaume Stirnemann and Hynes, James T and Laage, Damien} } @article {2010|1649, title = {Water reorientation, hydrogen-bond dynamics and 2D-IR spectroscopy next to an extended hydrophobic surface.}, journal = {Farad. Discuss.}, volume = {146}, year = {2010}, pages = {263{\textendash}281}, abstract = {

The dynamics of water next to hydrophobic groups is critical for several fundamental biochemical processes such as protein folding and amyloid fiber aggregation. Some biomolecular systems, like melittin or other membrane-associated proteins, exhibit extended hydrophobic surfaces. Due to the strain these surfaces impose on the hydrogen (H)-bond network, the water molecules shift from the clathrate-like arrangement observed around small solutes to an anticlathrate-like geometry with some dangling OH bonds pointing toward the surface. Here we examine the water reorientation dynamics next to a model hydrophobic surface through molecular dynamics simulations and analytic modeling. We show that the water OH bonds lying next to the hydrophobic surface fall into two subensembles with distinct dynamical reorientation properties. The first is the OH bonds tangent to the surface; these exhibit a behavior similar to the water OHs around small hydrophobic solutes, i.e. with a moderate reorientational slowdown explained by an excluded volume effect due to the surface. The second is the dangling OHs pointing toward the surface: these are not engaged in any H-bond, reorient much faster than in the bulk, and exhibit an unusual anisotropy decay which becomes negative for delays of a few picoseconds. The H-bond dynamics, i.e. the exchanges between the different configurations, and the resulting anisotropy decays are analyzed within the analytic extended jump model. We also show that a recent spectroscopy technique, two-dimensional time resolved vibrational spectroscopy (2D-IR), can be used to selectively follow the dynamics of dangling OHs, since these are spectrally distinct from H-bonded ones. By computing the first 2D-IR spectra of water next to a hydrophobic surface, we establish a connection between the spectral dynamics and the dynamical properties that we obtain directly from the simulations.

}, issn = {1359-6640}, author = {Guillaume Stirnemann and Rossky, Peter J and Hynes, James T and Laage, Damien} } @article {2009|1509, title = {{E}ts-1 p51 and p42 isoforms differentially modulate {S}tromelysin-1 promoter according to induced {D}{N}{A} bend orientation}, journal = {Nucleic Acids Res.}, volume = {37}, year = {2009}, month = {jul}, pages = {4341{\textendash}4352}, author = {Leprivier, G. and Baillat, D. and Begue, A. and Hartmann, B. and Aumercier, M.} } @article {2009|1605, title = {The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15 N chemical shifts}, journal = {Biophys. Chem.}, volume = {143}, number = {3}, year = {2009}, pages = {111{\textendash}123}, publisher = {Elsevier}, author = {Spichty, Martin and Antoine Taly and Hagn, Franz and Kessler, Horst and Barluenga, Sofia and Winssinger, Nicolas and Karplus, Martin} } @article {2009|1864, title = {Models for phosphatidylglycerol lipids put to a structural test}, journal = {J. Phys. Chem. B}, volume = {113}, number = {19}, year = {2009}, pages = {6958{\textendash}6963}, publisher = {Center for Molecular Modeling, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA. jhenin@cmm.chem.upenn.edu}, abstract = {Three atomistic empirical models for phosphatidylglycerol (PG) lipids are tested against structural data in the crystal and liquid crystal states. Simulations of the anhydrous crystal of dimyristoyl-phosphatidylglycerol (DMPG) show that only the CHARMM force field describes the conformation and interactions of PG head groups accurately. The other two models do not reproduce the native network of hydrogen bonds, suggesting the presence of biases in their conformational and nonbonded interaction properties. The CHARMM model is further validated in the biologically relevant liquid crystal phase by comparing experimental small-angle X-ray scattering spectra from DMPG unilamellar vesicles with data calculated from fluid bilayer simulations. The good agreement found in this model-free comparison implies that liquid crystal PG bilayers as described by CHARMM exhibit realistic bilayer thickness and lateral packing. Last, this model is used to simulate a fluid bilayer of palmitoyl-oleoyl-phosphatidylglycerol (POPG). The resulting view of the POPG bilayer structure is at variance with that proposed previously based on simulations, in particular, with respect to lateral packing of head groups and the role of counterions.}, keywords = {chemistry, Crystallography, Lipid Bilayers, Models, Molecular, Phosphatidylglycerols, Scattering, Small Angle, Water, X-Ray}, doi = {10.1021/jp900645z}, author = {J{\'e}r{\^o}me H{\'e}nin and Wataru Shinoda and Michael L Klein} } @article {2009|1438, title = {{A}n optimized extended {D}{N}{A} kappa {B} site that enhances plasmid {D}{N}{A} nuclear import and gene expression}, journal = {J. Gene Med.}, volume = {11}, year = {2009}, month = {may}, pages = {401{\textendash}411}, author = {Goncalves, C. and Ardourel, M. Y. and Decoville, M. and Breuzard, G. and Midoux, P. and Hartmann, B. and Pichon, C.} } @article {2009|1384, title = {New Insight into the interaction between erbin and smad3: a non-classical binding interface for the erbin PDZ domain}, journal = {Biochem. Biophys. Res. Commun.}, volume = {378}, number = {3}, year = {2009}, pages = {360{\textendash}365}, author = {N Deliot and Matthieu Chavent and C Nourry and P Lecine and C Arnaud and A Hermant and B Maigret and J.-P. Borg} } @inbook {2009|1568, title = {Nonequilibrium molecular dynamics simulation of photoinduced energy flow in peptides: theory meets experiment}, year = {2009}, publisher = {CRC Press}, organization = {CRC Press}, author = {Phuong Hoang Nguyen and P. Hamm and G. Stock}, editor = {D. Leitner and J. Straub} } @article {2009|1779, title = {Role of nucleic acid binding in Sir3p-dependent interactions with chromatin fibers.}, journal = {Biochemistry}, volume = {48}, number = {2}, year = {2009}, month = {jan}, pages = {276{\textendash}288}, publisher = {Department of Biological Sciences and Cell Differentiation and Development Center, Marshall University, Huntington, West Virginia 25755, USA.}, abstract = {

Recent studies of the mechanisms involved in the regulation of gene expression in eukaryotic organisms depict a highly complex process requiring a coordinated rearrangement of numerous molecules to mediate DNA accessibility. Silencing in Saccharomyces cerevisiae involves the Sir family of proteins. Sir3p, originally described as repressing key areas of the yeast genome through interactions with the tails of histones H3 and H4, appears to have additional roles in that process, including involvement with a DNA binding component. Our in vitro studies focused on the characterization of Sir3p-nucleic acid interactions and their biological functions in Sir3p-mediated silencing using binding assays, EM imaging, and theoretical modeling. Our results suggest that the initial Sir3p recruitment is partially DNA-driven, highly cooperative, and dependent on nucleosomal features other than histone tails. The initial step appears to be rapidly followed by the spreading of silencing using linker DNA as a track.

}, doi = {10.1021/bi801705g}, author = {Nicholas L Adkins and Steve J McBryant and Cotteka N Johnson and Jennifer M Leidy and Christopher L Woodcock and Charles H Robert and Jeffrey C Hansen and Philippe T Georgel} } @article {2009|1693, title = {Why water reorientation slows without iceberg formation around hydrophobic solutes}, journal = {J. Phys. Chem. B}, volume = {113}, year = {2009}, pages = {2428{\textendash}2435}, abstract = {

The dynamics of water molecules next to hydrophobic solutes is investigated, specifically addressing the recent controversy raised by the first time-resolved observations, which concluded that some water molecules are immobilized by hydrophobic groups, in strong contrast to previous NMR conclusions. Through molecular dynamics simulations and an analytic jump reorientation model, we identify the water reorientation mechanism next to a hydrophobic solute and provide evidence that no water molecules are immobilized by hydrophobic solutes. Their moderate rotational slowdown compared to bulk water (e.g., by a factor of less than 2 at low solute concentration) is mainly due to slower hydrogen-bond exchange. The slowdown is quantitatively described by a solute excluded volume effect at the transition state for the key hydrogen-bond exchange in the reorientation mechanism. We show that this picture is consistent with both ultrafast anisotropy and NMR experimental results and that the transition state excluded volume theory yields quantitative predictions of the rotational slowdown for diverse hydrophobic solutes of varying size over a wide concentration range. We also explain why hydrophobic groups slow water reorientation less than do some hydrophilic groups.

}, author = {Laage, Damien and Guillaume Stirnemann and Hynes, James T.} } @article {2008|1468, title = {Construction of the free energy landscape of biomolecules via dihedral angle principal component analysis}, journal = {J. Chem. Phys.}, volume = {128}, number = {24}, year = {2008}, month = {jun}, author = {Altis, Alexandros and Otten, Moritz and Phuong Hoang Nguyen and Hegger, Rainer and Stock, Gerhard} } @article {2008|1603, title = {Diffusion of glycerol through Escherichia coli aquaglyceroporin GlpF}, journal = {Biophys. J.}, volume = {94}, number = {3}, year = {2008}, pages = {832{\textendash}839}, abstract = {The glycerol uptake facilitator, GlpF, a major intrinsic protein found in Escherichia coli, selectively conducts water and glycerol across the inner membrane. The free energy landscape characterizing the assisted transport of glycerol by this homotetrameric aquaglyceroporin has been explored by means of equilibrium molecular dynamics over a timescale spanning 0.12 micros. To overcome the free energy barriers of the conduction pathway, an adaptive biasing force is applied to the glycerol molecule confined in each of the four channels. The results illuminate the critical role played by intramolecular relaxation on the diffusion properties of the permeant. These free energy calculations reveal that glycerol tumbles and isomerizes on a timescale comparable to that spanned by its adaptive-biasing-force-assisted conduction in GlpF. As a result, reorientation and conformational equilibrium of glycerol in GlpF constitute a bottleneck in the molecular simulations of the permeation event. A profile characterizing the position-dependent diffusion of the permeant has been determined, allowing reaction rate theory to be applied for investigating conduction kinetics based on the measured free energy landscape.}, keywords = {Aquaporins, Chemical, Computer Simulation, Diffusion, Escherichia coli Proteins, Glycerol, Ion Channel Gating, Models, Molecular, Molecular Conformation, Porosity}, doi = {10.1529/biophysj.107.115105}, author = {J{\'e}r{\^o}me H{\'e}nin and Emad Tajkhorshid and Klaus Schulten and Christophe Chipot} } @article {2008|1970, title = {Embedded cholesterol in the nicotinic acetylcholine receptor}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {105}, number = {38}, year = {2008}, pages = {14418{\textendash}14423}, publisher = {Center for Molecular Modeling, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA. grace@cmm.upenn.edu}, abstract = {The nicotinic acetylcholine receptor (nAChR) is a cation-selective channel central to both neuronal and muscular processes and is considered the prototype for ligand-gated ion channels, motivating a structural determination effort that spanned several decades [Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4 A resolution. J Mol Biol 346:967-989]. Purified nAChR must be reconstituted in a mixture containing cholesterol to function. Proposed modes of interaction between cholesterol and the protein range from specific binding to indirect membrane-mediated mechanisms. However, the underlying cause of nAChR sensitivity to cholesterol remains controversial, in part because the vast majority of functional studies were conducted before a medium resolution structure was reported. We show that the nAChR contains internal sites capable of containing cholesterol, whose occupation stabilizes the protein structure. We detect sites at the protein-lipid interface as conventionally predicted from functional data, as well as deeply buried sites that are not usually considered. Molecular dynamics simulations reveal that occupation of both superficial and deeply buried sites most effectively preserves the experimental structure; the structure collapses in the absence of bound cholesterol. In particular, we find that bound cholesterol directly supports contacts between the agonist-binding domain and the pore that are thought to be essential for activation of the receptor. These results likely apply to those other ion channels within the Cys-loop superfamily that depend on cholesterol, such as the GABA receptor.}, doi = {10.1073/pnas.0803029105}, author = {Grace Brannigan and J{\'e}r{\^o}me H{\'e}nin and Richard Law and Roderic G Eckenhoff and Michael L Klein} } @article {2008|1485, title = {Energy transport in peptide helices: A comparison between high- and low-energy excitations}, journal = {J. Phys. Chem. B}, volume = {112}, number = {30}, year = {2008}, month = {jul}, pages = {9091{\textendash}9099}, author = {Backus, Ellen H. G. and Phuong Hoang Nguyen and Botan, Virgiliu and Pfister, Rolf and Moretto, Alessandro and Crisma, Marco and Toniolo, Claudio and Stock, Gerhard and Hamm, Peter} } @article {2008|1439, title = {Importance of accurate DNA structures in solution: the Jun-Fos model.}, journal = {J. Mol. Biol.}, volume = {382}, number = {(4)}, year = {2008}, pages = {956{\textendash}70}, author = {Heddi, B and Foloppe, N and Oguey, C and Hartmann, B} } @article {2008|1662, title = {Insights on protein-DNA recognition by coarse grain modelling}, journal = {J. Comput. Chem.}, volume = {29}, year = {2008}, month = {nov}, pages = {2582{\textendash}92}, abstract = {

Coarse grain modelling of macromolecules is a new approach, potentially well adapted to answer numerous issues, ranging from physics to biology. We propose here an original DNA coarse grain model specifically dedicated to protein-DNA docking, a crucial, but still largely unresolved, question in molecular biology. Using a representative set of protein-DNA complexes, we first show that our model is able to predict the interaction surface between the macromolecular partners taken in their bound form. In a second part, the impact of the DNA sequence and electrostatics, together with the DNA and protein conformations on docking is investigated. Our results strongly suggest that the overall DNA structure mainly contributes in discriminating the interaction site on cognate proteins. Direct electrostatic interactions between phosphate groups and amino acid side chains strengthen the binding. Overall, this work demonstrates that coarse grain modeling can reveal itself a precious auxiliary for a general and complete description and understanding of protein-DNA association mechanisms.

}, doi = {10.1002/jcc.21014}, author = {Poulain, P and A Saladin and Hartmann, B and Chantal Pr{\'e}vost} } @article {2008|1515, title = {KNOTTIN: the knottin or inhibitor cystine knot scaffold in 2007}, journal = {Nucleic Acids Res.}, volume = {36}, number = {Sp. Iss. SI}, year = {2008}, month = {jan}, pages = {D314-D319}, keywords = {knottin}, author = {Gracy, Jerome and Le-Nguyen, Dung and Gelly, Jean-Christophe and Kaas, Quentin and Heitz, Annie and Chiche, Laurent} } @inbook {2008|1651, title = {Searching for Homology by Filaments of RecA-like Proteins}, booktitle = {Genome Dynamics \& Stability}, volume = {Recombination and Meiosis. Models, Means and Evolution}, number = {3}, year = {2008}, pages = {65{\textendash}89}, publisher = {Springer Verlag}, organization = {Springer Verlag}, edition = {Richard Egel and Dirk-Henner Lankenau}, address = {Berlin Heidelberg}, abstract = {

The recombinase proteins of the RecA family perform tasks that are essential for cell survival and for the maintenance of genetic diversity. They are able to rearrange genes in new combinations and to repair DNA double-strand breaks in an almost error-free fashion. Their function in homologous recombination is performed in an original way that has no equivalent in the DNA processing machinery: They form long helical filaments on a target DNA, capable of recognizing homologous DNA sequences in the genome and of exchanging DNA strands. How the DNA sequences are recognized during this process and how the DNA strands are exchanged remain matters of investigation. This chapter reviews the information that has been accumulated on recognition and strand exchange, together with the models that aim at organizing this data, viewed at different levels: that of the nucleus, the molecule, or the atom. Altogether, a picture begins to emerge on a multiscale dimension, which presents the search for homology as a complex process with important dynamic components.

}, author = {Chantal Pr{\'e}vost}, editor = {Richard Egel and Dirk Henner-Lankenau} } @article {2008|1484, title = {Structural Flexibility of a Helical Peptide Regulates Vibrational Energy Transport Properties}, journal = {J. Phys. Chem. B}, volume = {112}, number = {48}, year = {2008}, month = {dec}, pages = {15487{\textendash}15492}, author = {Backus, Ellen H. G. and Phuong Hoang Nguyen and Botan, Virgiliu and Moretto, Alessandro and Crisma, Marco and Toniolo, Claudio and Zerbe, Oliver and Stock, Gerhard and Hamm, Peter} } @article {2008|1866, title = {United-Atom Acyl Chains for {CHARMM} Phospholipids}, journal = {J. Phys. Chem. B.}, volume = {112}, number = {23}, year = {2008}, pages = {7008{\textendash}7015}, publisher = {Center for Molecular Modeling, Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, Pennsylvania 19104-6323, and Research Institute for Computational Sciences, National Institute of Advanced Industrial Science and Technol}, abstract = {In all-atom simulations of lipid membranes, explicit hydrogen atoms contained in the hydrocarbon region are described by a large number of degrees of freedom, although they convey only limited physical information. We propose an implicit-hydrogen model for saturated and monounsaturated acyl chains, aimed at complementing the all-atom CHARMM27 model for phospholipid headgroups. Torsional potentials and nonbonded parameters were fitted to reproduce experimental data and free energy surfaces of all-atom model systems. Comparative simulations of fluid-phase POPC bilayers were performed using the all-hydrogen force field and the present model. The hybrid model accelerates a typical bilayer simulation by about 50\% while sacrificing a minimal amount of detail with respect to the fully atomistic description. In addition, the united-atom description is energetically compatible with all-atom CHARMM models, making it suitable for simulations of complex membrane systems.}, doi = {10.1021/jp800687p}, author = {J{\'e}r{\^o}me H{\'e}nin and Wataru Shinoda and Michael L Klein} } @article {2007, title = {Dihedral angle principal component analysis of molecular dynamics simulations}, journal = {J. Chem. Phys.}, volume = {126}, number = {24}, year = {2007}, month = {jun}, author = {Altis, Alexandros and Phuong Hoang Nguyen and Hegger, Rainer and Stock, Gerhard} } @article {2007|1534, title = {Energy transport in peptide helices}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {104}, number = {31}, year = {2007}, month = {jul}, pages = {12749{\textendash}12754}, author = {Botan, Virgiliu and Backus, Ellen H. G. and Pfister, Rolf and Moretto, Alessandro and Crisma, Marco and Toniolo, Claudio and Phuong Hoang Nguyen and Stock, Gerhard and Hamm, Peter} } @article {2007|1522, title = {How complex is the dynamics of peptide folding?}, journal = {Phys. Rev. Lett.}, volume = {98}, number = {2}, year = {2007}, month = {jan}, author = {Hegger, Rainer and Altis, Alexandros and Phuong Hoang Nguyen and Stock, Gerhard} } @article {2006|1860, title = {Conformational equilibrium in alanine-rich peptides probed by reversible stretching simulations}, journal = {J. Phys. Chem. B}, volume = {110}, number = {33}, year = {2006}, pages = {16718{\textendash}16723}, doi = {10.1021/jp0601116}, author = {J{\'e}r{\^o}me H{\'e}nin and Schulten, K. and Christophe Chipot} } @article {2006|1935, title = {HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcription.}, journal = {Mol. Cell}, volume = {22}, number = {5}, year = {2006}, month = {jun}, pages = {669{\textendash}679}, publisher = {Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Building 41, B602, Bethesda, Maryland 20892, USA.}, abstract = {Although histone deacetylases (HDACs) are generally viewed as corepressors, we show that HDAC1 serves as a coactivator for the glucocorticoid receptor (GR). Furthermore, a subfraction of cellular HDAC1 is acetylated after association with the GR, and this acetylation event correlates with a decrease in promoter activity. HDAC1 in repressed chromatin is highly acetylated, while the deacetylase found on transcriptionally active chromatin manifests a low level of acetylation. Acetylation of purified HDAC1 inactivates its deacetylase activity, and mutation of the critical acetylation sites abrogates HDAC1 function in vivo. We propose that hormone activation of the receptor leads to progressive acetylation of HDAC1 in vivo, which in turn inhibits the deacetylase activity of the enzyme and prevents a deacetylation event that is required for promoter activation. These findings indicate that HDAC1 is required for the induction of some genes by the GR, and this activator function is dynamically modulated by acetylation.}, keywords = {Acetylation, Amino Acid Sequence, Animals, Binding Sites, Cell Cycle Proteins, Chromatin, Down-Regulation, genetics/metabolism, Hela Cells, Histone Acetyltransferases, Histone Deacetylases, Humans, immunology/metabolism, metabolism}, doi = {10.1016/j.molcel.2006.04.019}, author = {Yi Qiu and Yingming Zhao and Matthias Becker and Sam John and Bhavin S Parekh and Suming Huang and Anindya Hendarwanto and Elisabeth D Martinez and Yue Chen and Hanxin Lu and Nicholas L Adkins and Diana A Stavreva and Malgorzata Wiench and Philippe T Geor} } @article {2006|1943, title = {Hfq variant with altered RNA binding functions}, journal = {Nucleic Acids Res.}, volume = {34}, number = {2}, year = {2006}, pages = {709{\textendash}720}, doi = {10.1093/nar/gkj464}, author = {Ziolkowska, K and Philippe Derreumaux and Folichon, M and Pellegrini, O and Regnier, P and Boni, IV and Hajnsdorf, E} } @article {2006|1794, title = {Hydrogen-bonding patterns of cholesterol in lipid membranes}, journal = {Chem. Phys. Lett.}, volume = {425}, year = {2006}, pages = {329{\textendash}335}, abstract = {Correlation between the rotation of the cholesterol hydroxyl group and the formation of hydrogen bonds with its lipid environment is examined through molecular dynamics (MD) simulations and compared with recently reported NMR experiments. All atom MD simulations of a fully hydrated 1:2 cholesterol-dimyristoylphosphatidylcholine bilayer have been performed. Precise reproduction of the cholesterol cell parameters via simulation of its P1-group crystal validates the force field utilized. The lipid-cholesterol hydrogen-bonding pattern reflects the coexistence of alternative dimer motifs with comparable conformer populations, in line with the estimated free energy differences for the rotamers of the cholesterol CO bond.}, url = {http://www.sciencedirect.com/science/article/B6TFN-4JYTJ8F-1/2/20363e602ea4fdd317abf97ba8e91987}, author = {J{\'e}r{\^o}me H{\'e}nin and Christophe Chipot} } @article {2006|1618, title = {Impact of the mutation A21G (Flemish variant) on Alzheimer{\textquoteright}s beta-amyloid dimers by molecular dynamics simulations}, journal = {Biophys. J.}, volume = {91}, number = {10}, year = {2006}, month = {nov}, pages = {3829{\textendash}3840}, doi = {10.1526/biophysj.106.090993}, author = {Huet, Alexis and Philippe Derreumaux} } @article {2006|1658, title = {Odorant Binding and Conformational Dynamics in the Odorant-binding Protein}, journal = {J. Biol. Chem.}, volume = {281}, number = {40}, year = {2006}, month = {oct}, pages = {29929{\textendash}29937}, abstract = {In mammals, the olfactory epithelium secretes odorant-binding proteins (OBPs), which are lipocalins found freely dissolved in the mucus layer protecting the olfactory neurons. OBPs may act as passive transporters of predominantly hydrophobic odorant molecules across the aqueous mucus layer, or they may play a more active role in which the olfactory neuronal receptor recognizes the OBP-ligand complex. To better understand the molecular events accompanying the initial steps in the olfaction process, we have performed molecular dynamics studies of rat and pig OBPs with the odorant molecule thymol. These calculations provide an atomic level description of conformational changes and pathway intermediates that remain difficult to study directly. A series of eight independent molecular dynamics trajectories of rat OBP permitted the observation of a consensus pathway for ligand unbinding and the calculation of the potential of mean force (PMF) along this path. Titration microcalorimetry confirmed the specific binding of thymol to this protein with a strong hydrophobic component. In both rat and pig OBPs we observed lipocalin strand pair opening in the presence of ligand, consistent with potential roles of these proteins in olfactive receptor recognition.}, doi = {10.1074/jbc.M604869200}, author = {Eric Hajjar and David Perahia and Helene D{\'e}bat and Claude Nespoulous and Charles H. Robert} } @article {2006|1604, title = {Probing a model of a {GPCR}/ligand complex in an explicit membrane environment: The human cholecystokinin-1 receptor}, journal = {Biophys. J.}, volume = {90}, number = {4}, year = {2006}, pages = {1232{\textendash}1240}, abstract = {A three-dimensional model structure of a complex formed by a G-protein-coupled receptor (GPCR) and an agonist ligand is probed and refined using molecular-dynamics simulations and free energy calculations in a realistic environment. The model of the human receptor of cholecystokinin associated to agonist ligand CCK9 was obtained from a synergistic procedure combining site-directed mutagenesis experiments and in silico modeling. The 31-ns molecular-dynamics simulation in an explicit membrane environment indicates that both the structure of the receptor and its interactions with the ligand are robust. Whereas the secondary structure of the {alpha}-helix bundle is well preserved, the region of the intracellular loops exhibits a significant flexibility likely to be ascribed to the absence of G-protein subunits in the model. New insight into the structural features of the binding pocket is gained, in particular, the interplay of the ligand with both the receptor and internal water molecules. Water-mediated interactions are shown to participate in the binding, hence, suggesting additional site-directed mutagenesis experiments. Accurate free energy calculations on mutated ligands provide differences in the receptor-ligand binding affinity, thus offering a direct, quantitative comparison to experiment. We propose that this detailed consistency-checking procedure be used as a routine refinement step of in vacuo GPCR models, before further investigation and application to structure-based drug design.}, url = {http://www.biophysj.org/cgi/content/abstract/90/4/1232}, author = {J{\'e}r{\^o}me H{\'e}nin and Maigret, B. and Mounir Tarek and Escrieut, C. and Fourmy, D. and Christophe Chipot} } @article {2006|1514, title = {Protein Peeling 2: a web server to convert protein structures into series of protein units}, journal = {Nucleic Acids Res.}, volume = {34}, number = {Sp. Iss. SI}, year = {2006}, month = {jul}, pages = {W75-W78}, author = {Gelly, J. -C. and Etchebest, C. and Hazout, S. and de Brevern, A. G.} } @article {2006|1386, title = {{\textquoteleft}Protein Peeling{\textquoteright}: an approach for splitting a 3D protein structure into compact fragments}, journal = {Bioinformatics}, volume = {22}, number = {2}, year = {2006}, pages = {129{\textendash}133}, author = {Gelly, JC and de Brevern, AG and Hazout, S} } @conference {2006|1421, title = {Yeast Naked DNA Spatial Organization Predisposes to Transcriptional Regulation}, booktitle = {International Conference on Computational Science and its Applications (ICCSA 2006)}, volume = {3984}, year = {2006}, month = {may}, pages = {222{\textendash}231}, address = {Glasgow, United Kingdom}, author = {O. Matte-Tailliez and J .H{\'e}risson and Nicolas F{\'e}rey and O. Magneau and P.-E. Gros and F. K{\'e}p{\`e}s and R. Gherbi} } @article {2005|1980, title = {The beta alpha beta alpha beta alpha elementary Supersecondary structure of the Rossmann fold from porcine lactate dehydrogenase exhibits characteristics of a molten globule}, journal = {Proteins: Struct., Funct., Bioinf.}, volume = {60}, number = {4}, year = {2005}, month = {sep}, pages = {740{\textendash}745}, doi = {10.1002/prot.20507}, author = {Coincon, M and Heitz, A and Chiche, L and Philippe Derreumaux} } @article {2005|1847, title = {Exploring the free energy landscape of a short peptide using an average force}, journal = {J. Chem. Phys.}, volume = {123}, year = {2005}, pages = {244906}, author = {Christophe Chipot and J{\'e}r{\^o}me H{\'e}nin} } @article {2005|1538, title = {Free energy landscape and folding mechanism of a beta-hairpin in explicit water: A replica exchange molecular dynamics study}, journal = {Proteins: Struct., Funct., Bioinf.}, volume = {61}, number = {4}, year = {2005}, month = {dec}, pages = {795{\textendash}808}, author = {Phuong Hoang Nguyen and Stock, G and Mittag, E and Hu, CK and Li, MS} } @article {2005|1405, title = {Immersive graph-based visualization and exploration of biological data relationships}, journal = {Data Sci. J.}, volume = {4}, year = {2005}, month = {mar}, pages = {189{\textendash}194}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @article {2005|1839, title = {Insights into the recognition and association of transmembrane $\alpha$-helices. {T}he free energy of $\alpha$-helix dimerization in glycophorin {A}}, journal = {J. Am. Chem. Soc.}, volume = {127}, number = {23}, year = {2005}, pages = {8478{\textendash}8484}, abstract = {The free energy of alpha-helix dimerization of the transmembrane (TM) region of glycophorin A was estimated from a 125-ns molecular dynamics (MD) simulation in a membrane mimetic. The free energy profile was obtained by allowing the TM helical segments to diffuse reversibly along the reaction pathway. Partition of the potential of mean force into free energy components illuminates the critical steps of alpha-helix recognition and association. At large separations, the TM segments are pushed together by the solvent, allowing initial, but not necessarily native, interhelical interactions to occur. This early recognition stage precedes the formation of native contacts, which is accompanied by a tilt of the helices, characteristic of the dimeric structure. This step is primarily driven by the van der Waals helix-helix interactions. Free energy perturbation calculations of the L75A and I76A point mutations reveal a disruption in helix-helix association due to a loss of favorable dispersion interactions. Additional MD simulations of the native TM dimer and of a single alpha-helix confirm that, prior to association, individual alpha-helices are independently stable, in agreement with the "two-stage" model of integral membrane protein folding.}, doi = {10.1021/ja050581y}, author = {J{\'e}r{\^o}me H{\'e}nin and A. Pohorille and Christophe Chipot} } @conference {2005|1422, title = {Visual data mining of genomic databases by immersive graph-based exploration}, booktitle = {international Conference on Computer Graphics and interactive Techniques in Australasia and South East Asia (GRAPHITE 2005 - ACM-ACMSIGRAPH Sponsored)}, year = {2005}, month = {nov}, pages = {143{\textendash}146}, address = {Dunedin - New Zealand}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @conference {2004|1815, title = {Combining Applications and Databases Integration Approaches in a Common Distributed Genomic Platform}, booktitle = {International CODATA Conference, The Information Society: New Horizons for Science}, year = {2004}, month = {nov}, publisher = {Tamkang University}, organization = {Tamkang University}, address = {Berlin, Germany}, author = {P.-E. Gros and J. H{\'e}risson and Nicolas F{\'e}rey and R. Gherbi} } @article {2004|1807, title = {The C-terminal domain of Escherichia coli Hfq increases the stability of the hexamer}, journal = {Eur. J. Biochem.}, volume = {271}, number = {7}, year = {2004}, month = {apr}, pages = {1258{\textendash}1265}, doi = {10.1111/j.1432-1033.2004.04026.x}, author = {Arluison, V and Folichon, M and Marco, S and Philippe Derreumaux and Pellegrini, O and Seguin, J and Hajnsdorf, E and Regnier, P} } @conference {2004|1420, title = {A Distributed Multimedia Database Visualization within An Immersive Environment for Bioinformatics}, booktitle = {International Symposium on Multimedia Software Engineering (ISMSE 2004 - IEEE)}, year = {2004}, month = {dec}, pages = {156{\textendash}159}, address = {Miami - USA}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @conference {2004|1425, title = {DNA in Virtuo: Visualization and Exploration of 3D Genomic Structures}, booktitle = {International Conference on Virtual Reality, Computer Graphics, Visualization and Interaction (Afrigraph 2005 - ACM-SIGRAPH sponsored)}, year = {2004}, month = {nov}, address = {Stellenbosch (Cap town), South Africa}, author = {J. H{\'e}risson and P.-E. Gros and Nicolas F{\'e}rey and O. Magneau and R. Gherbi} } @conference {2004|1419, title = {DNA in Virtuo: Visualization and Virtual Manipulation of 3D Genomic Structures}, booktitle = {International CODATA Conference, The Information Society: New Horizons for Science}, year = {2004}, month = {nov}, address = {Berlin, Germany}, author = {J. H{\'e}risson and P.-E. Gros and Nicolas F{\'e}rey and O. Magneau and R. Gherbi} } @article {2004|1462, title = {Exploration by visualization of numerical and textual genomic data}, journal = {Journal of Biological Physics and Chemistry}, volume = {4}, number = {2}, year = {2004}, month = {jun}, pages = {102{\textendash}110}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @conference {2004|1423, title = {GenoMEDIA, a Midlleware Platform for Distributed Genomic Information}, booktitle = {International Conference on Information \& Communication Technologies: from Theory to Applications (ICTTA 2004 - IEEE)}, year = {2004}, month = {apr}, address = {Damascus - Syria}, author = {P.-E. Gros and Nicolas F{\'e}rey and J. H{\'e}risson and R. Gherbi} } @conference {2004|1418, title = {Immersive Graph-based Visualization and Exploration of Biological Data}, booktitle = {International CODATA Conference - The Information Society: New Horizons for Science}, year = {2004}, month = {nov}, address = {Berlin - Germany}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @article {2004|1513, title = {The KNOTTIN website and database: a new information system dedicated to the knottin scaffold}, journal = {Nucleic Acids Res.}, volume = {32}, number = {Sp. Iss. SI}, year = {2004}, month = {jan}, pages = {D156-D159}, author = {Gelly, JC and Gracy, J and Kaas, Q and Le-Nguyen, D and Heitz, A and Chiche, L} } @article {2004|1846, title = {Overcoming free energy barriers using unconstrained molecular dynamics simulations}, journal = {J. Chem. Phys.}, volume = {121}, year = {2004}, pages = {2904{\textendash}2914}, author = {J{\'e}r{\^o}me H{\'e}nin and Christophe Chipot} } @article {2004|1404, title = {Squash inhibitors: From structural motifs to macrocyclic knottins}, journal = {Current Protein \& Peptide Science}, volume = {5}, number = {5}, year = {2004}, pages = {341{\textendash}349}, author = {Chiche, L and Heitz, A and Gelly, JC and Gracy, J and Chau, PTT and Ha, PT and Hernandez, JF and Le-Nguyen, D} } @article {2004|1787, title = {Structural characterization of VGVAPG, an elastin-derived peptide}, journal = {Biopolymers}, volume = {76}, number = {3}, year = {2004}, pages = {266{\textendash}280}, doi = {10.1002/bip.20029}, author = {Floquet, N and Hery-Huynh, S and Dauchez, M and Philippe Derreumaux and Tamburro, AM and Alix, AJP} } @conference {2004|1492, title = {Visualization and Exploration of Factual and Textual Genomic Data}, booktitle = {Journ{\'e}es Ouvertes de Biologie, Informatique et Math{\'e}matiques (JOBIM 2004)}, year = {2004}, month = {jun}, address = {Montr{\'e}al - Canada}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @article {2002|1902, title = {Structural modelling of the Sm-like protein Hfq from Escherichia coli}, journal = {J. Mol. Biol.}, volume = {320}, number = {4}, year = {2002}, month = {jul}, pages = {705{\textendash}712}, doi = {10.1016/S0022-2836(02)00548-X}, author = {Arluison, V and Philippe Derreumaux and Allemand, F and Folichon, M and Hajnsdorf, E and Regnier, P} } @article {2001|1461, title = {Induction-independent recruitment of CREB-binding protein to the c-fos serum response element through interactions between the bromodomain and Elk-1}, journal = {J. Biol. Chem.}, volume = {276}, number = {7}, year = {2001}, month = {feb}, pages = {5213{\textendash}5221}, author = {Nissen, LJ and Gelly, JC and Hipskind, RA} } @article {2001|1841, title = {Sheep prion protein synthetic peptide spanning helix 1 and beta-strand 2 (residues 142-166) shows beta-hairpin structure in solution}, journal = {J. Biol. Chem.}, volume = {276}, number = {49}, year = {2001}, pages = {46364{\textendash}46370}, author = {S. A. Kozin and G. Bertho and Alexey K Mazur and H. Rabesona and J. P. Girault and T. Haertle and M. Takahashi and P. Debey and G. H. Hoa} } @article {1995|1969, title = {Significance of bound water to local chain conformations in protein crystals}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {92}, number = {16}, year = {1995}, month = {aug}, pages = {7600{\textendash}7604}, author = {Robert, C H and Ho, P S} } @article {1994|1584, title = {The catalytic mechanism of {$\alpha$}-amylases based upon enzyme crystal structures and model building calculations}, journal = {Biochem. Biophys. Res. Commun.}, volume = {204}, year = {1994}, pages = {297{\textendash}302}, author = {Alexey K Mazur and R. Haser and F. Payan} } @article {1988|1858, title = {Enthalpy of dimerization of benzene in water}, journal = {J. Phys. Chem.}, volume = {92}, year = {1988}, pages = {3623{\textendash}3625}, author = {D. Hallen and I. Wadso and D. J. Wasserman and C. H. Robert and S. J. Gill} } @article {1985|1855, title = {Dry deposition of nitric acid to grass}, journal = {J. Geophys. Res.}, volume = {90}, year = {1985}, pages = {2085{\textendash}2090}, author = {B. A. Huebert and C. H. Robert} }