@article {2025, title = {Impact of multiple phosphorylations on the tau-R2/tubulin interface}, journal = {Biochemistry}, year = {2025}, abstract = {

The phosphorylation of the microtubule-associated tau protein plays a key role in the regulation of its physiological function. In particular, tau hyperphosphorylation affects its binding to the tubulin surface, destabilizing the tau-microtubule interface and leading to the accumulation of fibrillar aggregates in the brain. In this work, we performed classical molecular dynamics simulations for the tau-R2/tubulin assembly with various phosphorylation states of serines 285, 289, and 293. We analyze the resulting trajectories to obtain a detailed view of the protein interface in the complex and the impact of tau phosphorylations on the stability of this assembly and on the mobility of the tubulin disordered C-terminal tails (CTTs). We show how the tubulin CTTs help maintain the tau-R2 fragment on the tubulin surface despite the destabilizing effect induced by phosphorylations. Conversely, tau phosphorylation affects the CTTs\&$\#$39; flexibility and their potential activity as MAP-recruiting hooks. Furthermore, counterion-mediated bridges between the phosphate groups and tubulin glutamates also contribute to the binding of tau-R2 on the MT. Overall, the complex dynamics of this fuzzy phosphorylated assembly shed new light on the importance of the cytoplasmic environment in neurons in the context of Alzheimer\&$\#$39;s disease.

}, author = {Marien, Jules and Pr{\'e}vost, Chantal and S Sacquin-Mora} } @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|2167, title = {NP-collabs: Investigating counterion-mediated bridges in the multiply phosphorylated tau-R2 repeat}, journal = {J. Chem. Inf. Model.}, volume = {64}, year = {2024}, pages = {6570{\textendash}6582}, abstract = {

Tau is an intrinsically disordered (IDP) microtubule-associated protein (MAP) that plays a key part in microtubule assembly and organization. The function of tau can be regulated by multiple phosphorylation sites. These post-translational modifications are known to decrease the binding affinity of tau for microtubules, and abnormal tau phosphorylation patterns are involved in Alzheimer\&$\#$39;s disease. Using all-atom molecular dynamics simulations, we compared the conformational landscapes explored by the tau R2 repeat domain (which comprises a strong tubulin binding site) in its native state and with multiple phosphorylations on the S285, S289, and S293 residues, with four different standard force field (FF)/water model combinations. We find that the different parameters used for the phosphate groups (which can be more or less flexible) in these FFs and the specific interactions between bulk cations and water lead to the formation of a specific type of counterion bridge, termed nP-collab (for nphosphate collaboration, with n being an integer), where counterions form stable structures binding with two or three phosphate groups simultaneously. The resulting effect of nP-collabs on the tau-R2 conformational space differs when using sodium or potassium cations and is likely to impact the peptide overall dynamics and how this MAP interacts with tubulins. We also investigated the effect of phosphoresidue spacing and ionic concentration by modeling polyalanine peptides containing two phosphoserines located one-six residues apart. Three new metrics specifically tailored for IDPs (proteic Menger curvature, local curvature, and local flexibility) were introduced, which allow us to fully characterize the impact of nP-collabs on the dynamics of disordered peptides at the residue level.

}, author = {Marien, Jules and Pr{\'e}vost, Chantal and S Sacquin-Mora} } @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 {2024|2169, title = {Structural profiles of the full phagocyte NADPH oxidase unveiled by combining computational biology and experimental knowledge}, journal = {J. Biol. Chem.}, volume = {300}, year = {2024}, pages = {107943}, abstract = {

The phagocyte NADPH oxidase (NOX2) is an enzyme, crucial for innate immune defense, producing reactive oxygen species necessary for pathogen destruction. Its activation requires the assembly of soluble proteins (p47phox, p40phox, p67phox, and Rac) with the membrane-bound flavocytochrome b558 (cytb558). We combined circular-dichroism analyses, with decades of experimental data, to filter structural models of the NADPH oxidase complex generated by the artificial intelligence program AlphaFold2 (AF2). The predicted patterns tend to closely resemble the active states of the proteins, as shown by the compact structure of the cytb558, whose dehydrogenase domain is stabilized closer to the membrane. The modeling of the interaction of p47phox with cytb558, which is the initial assembly and activation steps of the NADPH oxidase, enables us to describe how the C terminus of p47phox interacts with the cytb558. Combining the AF2 cytb558-p47phox model and its classical molecular dynamics simulations, we highlighted new hydrophobic lipid insertions of p47phox, particularly at residues Trp80-Phe81 of its PX domain. The AF2 models also revealed the implications of intrinsically disordered regions, such as the fragment between the PX domain and the SH3 regions of p47phox, in ensuring distant protein-protein and membrane-protein interactions. Finally, the AF2 prediction of the cytb558-Trimera model highlighted the importance of leaving Rac1 as a separate protein to reach an active state of the NADPH oxidase complex. Altogether, our step-by-step approach provides a structural model of the active complex showing how disordered regions and specific lipid and protein interactions can enable and stabilize the multisubunit assembly.

}, keywords = {alphafold, Circular Dichroism, Computational biology, lipid-protein interaction, membrane protein, molecular modeling, NADPH oxidase, NOX2, p47(phox), p67(phox), protein assembly, trimera}, author = {Aimeur, Sana and Fas, Burcu Aykac and Serfaty, Xavier and Santuz, Hubert and S Sacquin-Mora and Bizouarn, Tania and Taly, Antoine and Baciou, Laura} } @article {2023|2163, title = {Best Practices of Using AI-Based Models in Crystallography and Their Impact in Structural Biology}, journal = {J Chem Inf Model}, year = {2023}, month = {Jun}, author = {Graille, M and S Sacquin-Mora and Antoine Taly} } @article {2023, title = {Conformational and mechanical stability of the isolated large subunit of membrane-bound [NiFe]-hydrogenase from Cupriavidus necator}, journal = {Frontiers in Microbiology}, volume = {13}, year = {2023}, abstract = {

Comprising at least a bipartite architecture, the large subunit of [NiFe]-hydrogenase harbors the catalytic nickel\–iron site while the small subunit houses an array of electron-transferring Fe-S clusters. Recently, some [NiFe]-hydrogenase large subunits have been isolated showing an intact and redox active catalytic cofactor. In this computational study we have investigated one of these metalloproteins, namely the large subunit HoxG of the membrane-bound hydrogenase from Cupriavidus necator (CnMBH), targeting its conformational and mechanical stability using molecular modelling and long all-atom Gaussian accelerated molecular dynamics (GaMD). Our simulations predict that isolated HoxG is stable in aqueous solution and preserves a large portion of its mechanical properties, but loses rigidity in regions around the active site, in contrast to the MBH heterodimer. Inspired by biochemical data showing dimerization of the HoxG protein and IR measurements revealing an increased stability of the [NiFe] cofactor in protein preparations with higher dimer content, corresponding simulations of homodimeric forms were also undertaken. While the monomeric subunit contains several flexible regions, our data predicts a regained rigidity in homodimer models. Furthermore, we computed the electrostatic properties of models obtained by enhanced sampling with GaMD, which displays a significant amount of positive charge at the protein surface, especially in solvent-exposed former dimer interfaces. These data offer novel insights on the way the [NiFe] core is protected from de-assembly and provide hints for enzyme anchoring to surfaces, which is essential information for further investigations on these minimal enzymes.

}, issn = {1664-302X}, doi = {10.3389/fmicb.2022.1073315}, url = {https://www.frontiersin.org/articles/10.3389/fmicb.2022.1073315}, author = {Dragelj, Jovan and Karafoulidi-Retsou, Chara and Katz, Sagie and Lenz, Oliver and Zebger, Ingo and Caserta, Giorgio and S Sacquin-Mora and Mroginski, Maria Andrea} } @article {2023|2162, title = {Editorial: In Celebration of Women in Science: Biological Modeling and Simulation}, journal = {Front Mol Biosci}, volume = {10}, year = {2023}, pages = {1175325}, author = {Aykac Fas, B and S Sacquin-Mora and Papaleo, E} } @article {2023|2166, title = {It Takes Tau to Tango: Investigating the Fuzzy Interaction between the R2-Repeat Domain and Tubulin C-Terminal Tails}, journal = {Biochemistry}, volume = {62}, year = {2023}, month = {Aug}, pages = {2492{\textendash}2502}, author = {Marien, J and Prevost, C and S Sacquin-Mora} } @article {2022, title = {Between Two Walls: Modeling the Adsorption Behavior of β-Glucosidase A on Bare and SAM-Functionalized Gold Surfaces.}, journal = {Langmuir}, volume = {38}, year = {2022}, month = {2022 Feb 01}, pages = {1313-1323}, abstract = {

The efficient immobilization of enzymes on surfaces remains a complex but central issue in the biomaterials field, which requires us to understand this process at the atomic level. Using a multiscale approach combining all-atom molecular dynamics and coarse-grain Brownian dynamics simulations, we investigated the adsorption behavior of β-glucosidase A (βGA) on bare and self-assembled monolayer (SAM)-functionalized gold surfaces. We monitored the enzyme position and orientation during the molecular dynamics (MD) trajectories and measured the contacts it forms with both surfaces. While the adsorption process has little impact on the protein conformation, it can nonetheless perturb its mechanical properties and catalytic activity. Our results show that compared to the SAM-functionalized surface, the adsorption of βGA on bare gold is more stable, but less specific, and more likely to disrupt the enzyme\&$\#$39;s function. This observation emphasizes the fact that the structural organization of proteins at the solid interface is a key point when designing devices based on enzyme immobilization, as one must find an acceptable stability-activity trade-off.

}, issn = {1520-5827}, doi = {10.1021/acs.langmuir.1c01774}, author = {Bourassin, Nicolas and Barbault, Florent and Marc Baaden and S Sacquin-Mora} } @article {2022|2159, title = {Design {\textendash} a new way to look at old molecules}, journal = {Journal of Integrative Bioinformatics}, volume = {19}, year = {2022}, pages = {20220020}, doi = {doi:10.1515/jib-2022-0020}, url = {https://doi.org/10.1515/jib-2022-0020}, author = {Davide Spalvieri and Anne-Marine Mauviel and Matthieu Lambert and Nicolas F{\'e}rey and S Sacquin-Mora and Matthieu Chavent and Marc Baaden} } @article {2022|2150, title = {Modeling the Dynamics of Protein-Protein Interfaces, How and Why?}, journal = {Molecules}, volume = {27}, year = {2022}, pages = {1841}, abstract = {

Protein-protein assemblies act as a key component in numerous cellular processes. Their accurate modeling at the atomic level remains a challenge for structural biology. To address this challenge, several docking and a handful of deep learning methodologies focus on modeling protein-protein interfaces. Although the outcome of these methods has been assessed using static reference structures, more and more data point to the fact that the interaction stability and specificity is encoded in the dynamics of these interfaces. Therefore, this dynamics information must be taken into account when modeling and assessing protein interactions at the atomistic scale. Expanding on this, our review initially focuses on the recent computational strategies aiming at investigating protein-protein interfaces in a dynamic fashion using enhanced sampling, multi-scale modeling, and experimental data integration. Then, we discuss how interface dynamics report on the function of protein assemblies in globular complexes, in fuzzy complexes containing intrinsically disordered proteins, as well as in active complexes, where chemical reactions take place across the protein-protein interface.

}, issn = {1420-3049}, doi = {10.3390/molecules27061841}, url = {https://www.mdpi.com/1420-3049/27/6/1841}, author = {Karaca, Ezgi and Pr{\'e}vost, Chantal and S Sacquin-Mora} } @article {2021, title = {Moving pictures: Reassessing docking experiments with a dynamic view of protein interfaces.}, journal = {Proteins}, year = {2021}, month = {2021 May 26}, abstract = {

The modeling of protein assemblies at the atomic level remains a central issue in structural biology, as protein interactions play a key role in numerous cellular processes. This problem is traditionally addressed using docking tools, where the quality of the models is based on their similarity to a single reference experimental structure. However, using a static reference does not take into account the dynamic quality of the protein interface. Here, we used all-atom classical Molecular Dynamics simulations to investigate the stability of the reference interface for three complexes that previously served as targets in the CAPRI competition. For each one of these targets, we also ran MD simulations for ten models that are distributed over the High, Medium and Acceptable accuracy categories. To assess the quality of these models from a dynamic perspective, we set up new criteria which take into account the stability of the reference experimental protein interface. We show that, when the protein interfaces are allowed to evolve along time, the original ranking based on the static CAPRI criteria no longer holds as over 50\% of the docking models undergo a category change (which can be either toward a better or a lower accuracy group) when reassessing their quality using dynamic information.

}, issn = {1097-0134}, doi = {10.1002/prot.26152}, author = {Chantal Pr{\'e}vost and S Sacquin-Mora} } @article {2021|2146, title = {When Order Meets Disorder: Modeling and Function of the Protein Interface in Fuzzy Complexes}, journal = {Biomolecules}, volume = {11}, year = {2021}, pages = {1529}, abstract = {

The degree of proteins structural organization ranges from highly structured, compact folding to intrinsic disorder, where each degree of self-organization corresponds to specific functions: well-organized structural motifs in enzymes offer a proper environment for precisely positioned functional groups to participate in catalytic reactions; at the other end of the self-organization spectrum, intrinsically disordered proteins act as binding hubs via the formation of multiple, transient and often non-specific interactions. This review focusses on cases where structurally organized proteins or domains associate with highly disordered protein chains, leading to the formation of interfaces with varying degrees of fuzziness. We present a review of the computational methods developed to provide us with information on such fuzzy interfaces, and how they integrate experimental information. The discussion focusses on two specific cases, microtubules and homologous recombination nucleoprotein filaments, where a network of intrinsically disordered tails exerts regulatory function in recruiting partner macromolecules, proteins or DNA and tuning the atomic level association. Notably, we show how computational approaches such as molecular dynamics simulations can bring new knowledge to help bridging the gap between experimental analysis, that mostly concerns ensemble properties, and the behavior of individual disordered protein chains that contribute to regulation functions.

}, issn = {2218-273X}, doi = {10.3390/biom11101529}, url = {https://www.mdpi.com/2218-273X/11/10/1529}, author = {S Sacquin-Mora and Chantal Pr{\'e}vost} } @article {2020|2144, title = {Implicit Modeling of the Impact of Adsorption on Solid Surfaces for Protein Mechanics and Activity with a Coarse-Grained Representation}, journal = {J Phys Chem B}, volume = {124}, year = {2020}, month = {Oct}, pages = {8516{\textendash}8523}, author = {Bourassin, N. and Marc Baaden and Lojou, E. and S Sacquin-Mora} } @article {2020, title = {Protein Interaction Energy Landscapes are Shaped by Functional and also Non-functional Partners.}, journal = {J Mol Biol}, volume = {432}, year = {2020}, month = {2020 Feb 14}, pages = {1183-1198}, abstract = {

In the crowded cell, a strong selective pressure operates on the proteome to limit the competition between functional and non-functional protein-protein interactions. We developed an original theoretical framework in order to interrogate how this competition constrains the behavior of proteins with respect to their partners or random encounters. Our theoretical framework relies on a two-dimensional (2D) representation of interaction energy landscapes, with 2D energy maps, which reflect in a synthetic way the spatial distribution of the interaction propensity of a protein surface for another protein. We realized the interaction propensity mapping of proteins\&$\#$39; surfaces in interaction with functional and arbitrary partners and asked whether the distribution of their interaction propensity is conserved during evolution. Therefore, we performed several thousands of cross-docking simulations to systematically characterize the energy landscapes of 103 proteins interacting with different sets of homologs, corresponding to their functional partner\&$\#$39;s family or arbitrary protein families. Then, we systematically compared the energy maps resulting from the docking of each protein with the different protein families of the dataset. Strikingly, we show that the interaction propensity not only of the binding sites but also of the rest of the surface is conserved for docking partners belonging to the same protein family. Interestingly, this observation holds for docked proteins corresponding to true but also arbitrary partners. Our theoretical framework enables the characterization of the energy behavior of a protein in interaction with hundreds of proteins and opens the way for the characterization of the behavior of proteins in a specific environment.

}, issn = {1089-8638}, doi = {10.1016/j.jmb.2019.12.047}, author = {Schweke, Hugo and Mucchielli, Marie-H{\'e}l{\`e}ne and S Sacquin-Mora and Bei, Wanying and Lopes, Anne} } @article {2019|2061, title = {Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins.}, journal = {J R Soc Interface}, volume = {16}, year = {2019}, month = {2019 Jul 26}, pages = {20190075}, abstract = {

Dynamics are a key feature of protein function, and this is especially true of gating residues, which occupy cavity or tunnel lining positions in the protein structure, and will reversibly switch between open and closed conformations in order to control the diffusion of small molecules within a protein\&$\#$39;s internal matrix. Earlier work on globins and hydrogenases have shown that these gating residues can be detected using a multiscale scheme combining all-atom classic molecular dynamics simulations and coarse-grain calculations of the resulting conformational ensemble mechanical properties. Here, we show that the structural variations observed in the conformational ensembles produced by NMR spectroscopy experiments are sufficient to induce noticeable mechanical changes in a protein, which in turn can be used to identify residues important for function and forming a mechanical nucleus in the protein core. This new approach, which combines experimental data and rapid coarse-grain calculations and no longer needs to resort to time-consuming all-atom simulations, was successfully applied to five different protein families.

}, issn = {1742-5662}, doi = {10.1098/rsif.2019.0075}, author = {S Sacquin-Mora} } @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 {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|2045, title = {Hidden partners: Using cross-docking calculations to predict binding sites for proteins with multiple interactions}, journal = {Proteins: Structure, Function, and Bioinformatics}, volume = {00}, year = {2018}, pages = {1-15}, chapter = {1}, abstract = {

Abstract Protein-protein interactions control a large range of biological processes and their identification is essential to understand the underlying biological mechanisms. To complement experimental approaches, in silico methods are available to investigate protein-protein interactions. Cross-docking methods, in particular, can be used to predict protein binding sites. However, proteins can interact with numerous partners and can present multiple binding sites on their surface, which may alter the binding site prediction quality. We evaluate the binding site predictions obtained using complete cross-docking simulations of 358 proteins with 2 different scoring schemes accounting for multiple binding sites. Despite overall good binding site prediction performances, 68 cases were still associated with very low prediction quality, presenting individual area under the specificity-sensitivity ROC curve (AUC) values below the random AUC threshold of 0.5, since cross-docking calculations can lead to the identification of alternate protein binding sites (that are different from the reference experimental sites). For the large majority of these proteins, we show that the predicted alternate binding sites correspond to interaction sites with hidden partners, that is, partners not included in the original cross-docking dataset. Among those new partners, we find proteins, but also nucleic acid molecules. Finally, for proteins with multiple binding sites on their surface, we investigated the structural determinants associated with the binding sites the most targeted by the docking partners.

}, keywords = {alternate partners, binding site predictions, docking, multiple binding sites, protein-protein interfaces}, doi = {10.1002/prot.25506}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/prot.25506}, author = {Nathalie Lagarde and Alessandra Carbone and S Sacquin-Mora} } @article {2018|2047, title = {Mechanical variations in proteins with large-scale motions highlight the formation of structural locks}, journal = {Journal of Structural Biology}, year = {2018}, keywords = {Coarse-grain simulations, Elastic network model, Protein domain motion, Proteins mechanics}, issn = {1047-8477}, doi = {https://doi.org/10.1016/j.jsb.2018.05.006}, url = {http://www.sciencedirect.com/science/article/pii/S1047847718301308}, author = {S Sacquin-Mora} } @article {2018|2044, title = {Meet-U: Educating through research immersion}, journal = {PLOS Computational Biology}, volume = {14}, year = {2018}, month = {03}, pages = {1-10}, abstract = {

We present a new educational initiative called Meet-U that aims to train students for collaborative work in computational biology and to bridge the gap between education and research. Meet-U mimics the setup of collaborative research projects and takes advantage of the most popular tools for collaborative work and of cloud computing. Students are grouped in teams of 4\–5 people and have to realize a project from A to Z that answers a challenging question in biology. Meet-U promotes \"coopetition,\" as the students collaborate within and across the teams and are also in competition with each other to develop the best final product. Meet-U fosters interactions between different actors of education and research through the organization of a meeting day, open to everyone, where the students present their work to a jury of researchers and jury members give research seminars. This very unique combination of education and research is strongly motivating for the students and provides a formidable opportunity for a scientific community to unite and increase its visibility. We report on our experience with Meet-U in two French universities with master\’s students in bioinformatics and modeling, with protein\–protein docking as the subject of the course. Meet-U is easy to implement and can be straightforwardly transferred to other fields and/or universities. All the information and data are available at www.meet-u.org.

}, doi = {10.1371/journal.pcbi.1005992}, url = {https://doi.org/10.1371/journal.pcbi.1005992}, author = {Abdollahi, Nika and Albani, Alexandre and Anthony, Eric and Baud, Agnes and Cardon, M{\'e}lissa and Clerc, Robert and Czernecki, Dariusz and Conte, Romain and David, Laurent and Delaune, Agathe and Djerroud, Samia and Fourgoux, Pauline and Guiglielmoni, Nad{\`e}ge and Laurentie, Jeanne and Lehmann, Nathalie and Lochard, Camille and Montagne, R{\'e}mi and Myrodia, Vasiliki and Opuu, Vaitea and Parey, Elise and Polit, L{\'e}lia and Priv{\'e}, Sylvain and Quignot, Chlo{\'e} and Ruiz-Cuevas, Maria and Sissoko, Mariam and Sompairac, Nicolas and Vallerix, Audrey and Verrecchia, Violaine and Delarue, Marc and Gu{\'e}rois, Raphael and Ponty, Yann and S Sacquin-Mora and Carbone, Alessandra and Froidevaux, Christine and Le Crom, St{\'e}phane and Lespinet, Olivier and Weigt, Martin and Abboud, Samer and Bernardes, Juliana and Bouvier, Guillaume and Dequeker, Chlo{\'e} and Ferr{\'e}, Arnaud and Fuchs, Patrick and Lelandais, Ga{\"e}lle and Poulain, Pierre and Richard, Hugues and Schweke, Hugo and Laine, Elodie and Lopes, Anne} } @article {2017|2020, title = {Determinants of neuroglobin plasticity highlighted by joint coarse-grained simulations and high pressure crystallography}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {May}, pages = {1858}, author = {Colloc{\textquoteright}h, N. and S Sacquin-Mora and Avella, G. and Dhaussy, A. C. and Prange, T. and Vallone, B. and Girard, E.} } @article {2017, title = {Mobility and core-protein binding patterns of disordered C-terminal tails in β-tubulin isotypes.}, journal = {Biochemistry}, volume = { 56}, year = {2017}, pages = {1746{\textendash}1756}, chapter = {1746}, abstract = {

Although they play a significant part in the regulation of microtubule structure, dynamics and function, the disordered C-terminal tails of tubulin remain invisible to experimental structural methods and do not appear in the crystallographic structures that are currently available in the Protein Data Bank. Interestingly, these tails concentrate most of the sequence variability between tubulin isotypes, and are the sites of the principal post-translational modifications undergone by this protein. Using homology modeling, we developed two complete models for the human αI/βI and αI/βIII tubulin isotypes that include their C-terminal tails. We then investigated the conformational variability of the two β-tails using long time-scale classical Molecular Dynamics (MD) simulations that revealed similar features, notably the unexpected presence of common anchoring regions on the surface of the tubulin dimer, but also distinctive mobility or interaction patterns, some of which could be related to the tail lengths and charge distributions. We also observed in our simulations that the C-terminal tail from the βI isotype, but not the βIII, formed contacts in the putative binding site of a recently discovered peptide that disrupts microtubule formation in glioma cells. Hindering the binding site in the βI isotype would be consistent with this peptide\’s preferential disruption of microtubule formation in glioma, whose cells overexpress βIII, compared to normal glial cells. While these observations need to be confirmed with more intensive sampling, our study opens up new perspectives for the development of isotype-specific chemotherapy drugs.

}, doi = {10.1021/acs.biochem.6b00988}, author = {Laurin, Yoann and Eyer, Joel and Charles H. Robert and Chantal Pr{\'e}vost and S Sacquin-Mora} } @inbook {2016|1721, title = {Bridging Enzymatic Structure Function via Mechanics: A Coarse-Grain Approach}, booktitle = {Methods in Enzymology}, year = {2016}, pages = {227{\textendash}248}, publisher = {Academic Press}, organization = {Academic Press}, keywords = {Coarse-grain simulations}, issn = {0076-6879}, doi = {10.1016/bs.mie.2016.05.022}, url = {http://www.sciencedirect.com/science/article/pii/S007668791630057X}, author = {S Sacquin-Mora} } @article {2016|1759, title = {Great interactions: How binding incorrect partners can teach us about protein recognition and function}, journal = {Proteins: Struct., Funct., Bioinf.}, year = {2016}, pages = {n/a-n/a}, keywords = {binding sites prediction, coarse grain models, docking, protein-protein interaction, protein-protein interfaces}, issn = {1097-0134}, doi = {10.1002/prot.25086}, author = {Vamparys, Lydie and B. Laurent and Carbone, A. and S Sacquin-Mora} } @article {2015|1766, title = {Docking Peptides on Proteins: How to Open a Lock, in the Dark, with a Flexible Key}, journal = {Structure}, volume = {23}, number = {8}, year = {2015}, month = {aug}, pages = {1373{\textendash}1374}, doi = {10.1016/j.str.2015.07.004}, author = {S Sacquin-Mora and Chantal Pr{\'e}vost} } @article {2015|1833, title = {{F}old and flexibility: what can proteins{\textquoteright} mechanical properties tell us about their folding nucleus?}, journal = {J. R. Soc. Interface}, volume = {12}, number = {112}, year = {2015}, month = {nov}, author = {S Sacquin-Mora} } @article {2015|1586, title = {Investigating the Structural Variability and Binding Modes of the Glioma Targeting NFL-TBS.40-63 Peptide on Tubulin}, journal = {Biochemistry}, volume = {54}, number = {23}, year = {2015}, month = {jun}, pages = {3660{\textendash}3669}, doi = {10.1021/acs.biochem5b00146}, author = {Laurin, Y. and Savarin, P. and Charles H. Robert and M. Takahashi and Eyer, J. and Chantal Pr{\'e}vost and S Sacquin-Mora} } @article {2014|1931, title = {Assessing the effect of dynamics on the closed-loop protein-folding hypothesis}, journal = {Journal of the Royal Society Interface}, volume = {11}, number = {91}, year = {2014}, pages = {20130935}, doi = {10.1098/rsif.2013.0935}, url = {http://rsif.royalsocietypublishing.org/content/11/91/20130935.abstract}, author = {Chintapalli, Sree V. and Illingworth, Christopher J. R. and Upton, Graham J. G. and S Sacquin-Mora and Reeves, Philip J. and Mohammedali, Hani S. and Reynolds, Christopher A.} } @article {2014|1937, title = {Motions and mechanics: investigating conformational transitions in multi-domain proteins with coarse-grain simulations}, journal = {Mol. Simul.}, volume = {40}, number = {1-3}, year = {2014}, month = {jan}, pages = {229{\textendash}236}, doi = {10.1080/08927022.2013.843176}, author = {S Sacquin-Mora} } @article {2014|2015, title = {Multiscale Simulations Give Insight into the Hydrogen In and Out Pathways of [NiFe]-Hydrogenases from Aquifex aeolicus and Desulfovibrio fructosovorans}, journal = {J. Phys. Chem. B}, volume = {118}, number = {48}, year = {2014}, month = {dec}, pages = {13800{\textendash}13811}, doi = {10.1021/jp5089965}, author = {Oteri, F and Marc Baaden and Lojou, E and S Sacquin-Mora} } @article {2014|1518, title = {{T}he weak, fluctuating, dipole moment of membrane-bound hydrogenase from {A}quifex aeolicus accounts for its adaptability to charged electrodes}, journal = {Phys. Chem. Chem. Phys.}, volume = {16}, number = {23}, year = {2014}, month = {may}, pages = {11318{\textendash}11322}, author = {Oteri, F and Ciaccafava, A and Poulpiquet, A and Marc Baaden and Lojou, E and S Sacquin-Mora} } @article {2013|1700, title = {Heme orientation modulates histidine dissociation and ligand binding kinetics in the hexacoordinated human neuroglobin}, journal = {J. Biol. Inorg. Chem.}, volume = {18}, number = {1}, year = {2013}, pages = {111{\textendash}122}, doi = {10.1007/s00775-012-0956-2}, author = {Bocahut, A. and Derrien, V. and Bernad, S. and Sebban, P. and S Sacquin-Mora and Guittet, E. and Lescop, E.} } @article {2013|1961, title = {Protein-protein interactions in a crowded environment: an analysis via cross-docking simulations and evolutionary information}, journal = {Plos Comput. Biol.}, volume = {9}, number = {12}, year = {2013}, month = {dec}, pages = {e1003369}, doi = {10.1371/journal.pcbi.1003369}, url = {http://hal.inria.fr/hal-00875116}, author = {Lopes, Anne and S Sacquin-Mora and Dimitrova, Viktoriya and Laine, Elodie and Ponty, Yann and Carbone, Alessandra} } @article {2012|2016, title = {{T}hermal fluctuations of haemoglobin from different species: adaptation to temperature via conformational dynamics}, journal = {J. R. Soc. Interface}, volume = {9}, number = {76}, year = {2012}, month = {nov}, pages = {2845{\textendash}2855}, doi = {10.1098/rsif.2012.0364}, author = {Stadler, A. M. and Garvey, C. J. and Bocahut, A. and S Sacquin-Mora and Digel, I. and Schneider, G. J. and Natali, F. and Artmann, G. M. and Zaccai, G.} } @mastersthesis {2011|1574, title = {Coarse-grain models for proteins: Mechanical properties and interactions}, year = {2011}, note = {HDR d{\'e}livr{\'e}e par l{\textquoteright}UFR Sciences du Vivant}, month = {dec}, school = {Universit{\'e} Paris-Diderot - Paris VII}, type = {phdHabilitation {\`a} diriger des recherches}, keywords = {Computational biology, docking, elastic networks, interactions prot{\'e}iques, m{\'e}canique des prot{\'e}ines, Mod{\'e}lisation mol{\'e}culaire, protein interactions, protein mechanics, r{\'e}seau {\'e}lastique}, url = {https://tel.archives-ouvertes.fr/tel-00652917}, author = {S Sacquin-Mora} } @article {2011|1612, title = {Enzyme Closure and Nucleotide Binding Structurally Lock Guanylate Kinase}, journal = {Biophys. J.}, volume = {101}, number = {6}, year = {2011}, pages = {1440{\textendash}1449}, doi = {10.1016/j.bpj.2011.07.048}, author = {Delalande, O. and S Sacquin-Mora and Marc Baaden} } @article {2011|1446, title = {{F}rontier residues lining globin internal cavities present specific mechanical properties}, journal = {J. Am. Chem. Soc.}, volume = {133}, year = {2011}, month = {jun}, pages = {8753{\textendash}8761}, author = {Bocahut, A. and Bernad, S. and Sebban, P. and S Sacquin-Mora} } @article {2010|1613, title = {Functional Modes and Residue Flexibility Control the Anisotropic Response of Guanylate Kinase to Mechanical Stress}, journal = {Biophys. J.}, volume = {99}, number = {10}, year = {2010}, pages = {3412{\textendash}3419}, doi = {10.1016/j.bpj.2010.09.026}, author = {S Sacquin-Mora and Delalande, O. and Marc Baaden} } @article {2009|1442, title = {{C}harge {R}ecombination {K}inetics and {P}rotein {D}ynamics in {W}ild {T}ype and {C}arotenoid-less {B}acterial {R}eaction {C}enters: {S}tudies in {T}rehalose {G}lasses}, journal = {J. Phys. Chem. B}, volume = {113}, year = {2009}, month = {jul}, pages = {10389{\textendash}1398}, author = {Francia, F. and Malferrari, M. and S Sacquin-Mora and Venturoli, G.} } @book {2009|1567, title = {Coarse-graining protein mechanics}, volume = {Coarse-Graining of Condensed Phase and Biomolecular Systems}, year = {2009}, publisher = {Taylor and Francis}, organization = {Taylor and Francis}, author = {R Lavery and S Sacquin-Mora}, editor = {G. Voth} } @article {2009|1959, title = {Joint Evolutionary Trees: A Large-Scale Method To Predict Protein Interfaces Based on Sequence Sampling}, journal = {Plos Comput. Biol.}, volume = {5}, number = {1}, year = {2009}, month = {jan}, pages = {e1000267}, doi = {10.1371/journal.pcbi.1000267}, url = {http://dx.doi.org/10.1371\%2Fjournal.pcbi.1000267}, author = {Engelen, Stefan and Trojan, Ladislas A. and S Sacquin-Mora and Lavery, Richard and Carbone, Alessandra} } @article {2009|1799, title = {{M}odeling the {M}echanical {R}esponse of {P}roteins to {A}nisotropic {D}eformation}, journal = {Chemphyschem}, volume = {10}, number = {1}, year = {2009}, month = {jan}, pages = {115{\textendash}118}, doi = {10.1002/cphc.200800480}, author = {S Sacquin-Mora and Lavery, R.} } @article {2009|1443, title = {{R}elating the {D}iffusion of {S}mall {L}igands in {H}uman {N}euroglobin to {I}ts {S}tructural and {M}echanical {P}roperties}, journal = {J. Phys. Chem. B}, volume = {113}, number = {50}, year = {2009}, month = {nov}, pages = {16257{\textendash}16267}, author = {Bocahut, A. and Bernad, S. and Sebban, P. and S Sacquin-Mora} } @article {2008|1710, title = {Identification of Protein Interaction Partners and Protein-Protein Interaction Sites}, journal = {J. Mol. Biol.}, volume = {382}, number = {5}, year = {2008}, pages = {1276{\textendash}1289}, doi = {10.1016/j.jmb.2008.08.002}, author = {S Sacquin-Mora and Carbone, A. and Richard Lavery} } @article {2007|1984, title = {Locating the active sites of enzymes using mechanical properties}, journal = {Proteins: Struct., Funct., Bioinf.}, volume = {67}, number = {2}, year = {2007}, month = {may}, pages = {350{\textendash}359}, doi = {10.1002/prot.21353}, author = {S Sacquin-Mora and Laforet, Emilie and Lavery, Richard} } @article {2007|1588, title = {Probing the flexibility of the bacterial reaction center: The wild-type protein is more rigid than two site-specific mutants}, journal = {Biochemistry}, volume = {46}, number = {51}, year = {2007}, month = {dec}, pages = {14960{\textendash}14968}, doi = {10.1021/bi7004416}, author = {S Sacquin-Mora and Sebban, P. and Derrien, V. and Frick, B. and Richard Lavery and Alba-Simionesco, C.} } @article {2007|1868, title = {Protein mechanics: a route from structure to function}, journal = {Journal of Biosciences}, volume = {32}, number = {5, Sp. Iss. SI}, year = {2007}, month = {aug}, pages = {891{\textendash}898}, doi = {10.1007/s12038-007-0089-x}, author = {Lavery, Richard and S Sacquin-Mora} } @article {2006|1619, title = {Investigating the local flexibility of functional residues in hemoproteins}, journal = {Biophys. J.}, volume = {90}, number = {8}, year = {2006}, pages = {2706{\textendash}2717}, doi = {10.1529/biophysj.105.074997}, author = {S Sacquin-Mora and Richard Lavery} } @article {2004|1878, title = {Torsion-induced phase transitions in fluids confined between chemically decorated substrates}, journal = {J. Chem. Phys.}, volume = {121}, number = {18}, year = {2004}, month = {nov}, pages = {9077{\textendash}9086}, doi = {10.1063/1.1804154}, author = {S Sacquin-Mora and Fuchs, AH and Schoen, M} } @article {2003|1706, title = {Fluid phase transitions at chemically heterogeneous, nonplanar solid substrates: Surface versus confinement effects}, journal = {J. Chem. Phys.}, volume = {118}, number = {3}, year = {2003}, month = {jan}, pages = {1453{\textendash}1465}, doi = {10.1063/1.1529683}, author = {S Sacquin-Mora and Schoen, M. and Fuchs, A. H.} } @mastersthesis {2003|1561, title = {Fluide nanoconfines dans des systemes de basse symetrie : Simulations et Theorie}, year = {2003}, school = {Universit{\'e} Paris XI, Orsay}, type = {phd}, author = {S Sacquin-Mora} } @article {2003|1957, title = {Nanoscopic liquid bridges exposed to a torsional strain}, journal = {Physical Review E}, volume = {68}, number = {6, Part 2}, year = {2003}, month = {dec}, pages = {066103}, doi = {10.1103/PhysRevE.68.066103}, author = {S Sacquin-Mora and Fuchs, AH and Schoen, M} } @article {2002|1726, title = {Fluids confined by nanopatterned substrates of low symmetry}, journal = {Mol. Phys.}, volume = {100}, number = {18}, year = {2002}, month = {sep}, pages = {2971{\textendash}2982}, doi = {10.1080/00268970210121632}, author = {S Sacquin-Mora and Schoen, M. and Fuchs, A. H.} }