@article {2019|2122, title = {Modelling lipid systems in fluid with Lattice Boltzmann Molecular Dynamics simulations and hydrodynamics}, journal = {Scientific Reports}, volume = {9}, year = {2019}, pages = {16450}, abstract = {

In this work we present the coupling between Dry Martini, an efficient implicit solvent coarse-grained model for lipids, and the Lattice Boltzmann Molecular Dynamics (LBMD) simulation technique in order to include naturally hydrodynamic interactions in implicit solvent simulations of lipid systems. After validating the implementation of the model, we explored several systems where the action of a perturbing fluid plays an important role. Namely, we investigated the role of an external shear flow on the dynamics of a vesicle, the dynamics of substrate release under shear, and inquired the dynamics of proteins and substrates confined inside the core of a vesicle. Our methodology enables future exploration of a large variety of biological entities and processes involving lipid systems at the mesoscopic scale where hydrodynamics plays an essential role, e.g. by modulating the migration of proteins in the proximity of membranes, the dynamics of vesicle-based drug delivery systems, or, more generally, the behaviour of proteins in cellular compartments.

}, isbn = {2045-2322}, doi = {10.1038/s41598-019-52760-y}, url = {https://doi.org/10.1038/s41598-019-52760-y}, author = {F. Brandner, Astrid and Timr, Stepan and Melchionna, Simone and Philippe Derreumaux and Marc Baaden and Sterpone, Fabio} } @article {2019|2120, title = {Multiscale Aggregation of the Amyloid Aβ16{\textendash}22 Peptide: From Disordered Coagulation and Lateral Branching to Amorphous Prefibrils}, journal = {The Journal of Physical Chemistry Letters}, volume = {10}, year = {2019}, pages = {1594-1599}, doi = {10.1021/acs.jpclett.9b00423}, url = {https://doi.org/10.1021/acs.jpclett.9b00423}, author = {Chiricotto, Mara and Melchionna, Simone and Philippe Derreumaux and Sterpone, Fabio} } @article {2018|2035, title = {Molecular Mechanism of Protein Unfolding under Shear: A Lattice Boltzmann Molecular Dynamics Study.}, journal = {J Phys Chem B}, volume = {122}, year = {2018}, month = {2018 Feb 08}, pages = {1573-1579}, abstract = {

Proteins are marginally stable soft-matter entities that can be disrupted using a variety of perturbative stresses, including thermal, chemical, or mechanical ones. Fluid under extreme flow conditions is a possible route to probe the weakness of biomolecules and collect information on the molecular cohesive interactions that secure their stability. Moreover, in many cases, physiological flow triggers the functional response of specialized proteins as occurring in blood coagulation or cell adhesion. We deploy the Lattice Boltzmann molecular dynamics technique based on the coarse-grained model for protein OPEP to study the mechanism of protein unfolding under Couette flow. Our simulations provide a clear view of how structural elements of the proteins are affected by shear, and for the simple study case, the β-hairpin, we exploited the analogy to pulling experiments to quantify the mechanical forces acting on the protein under shear.

}, issn = {1520-5207}, doi = {10.1021/acs.jpcb.7b10796}, author = {Sterpone, Fabio and Philippe Derreumaux and Melchionna, Simone} } @article {2018|2138, title = {Three Weaknesses for Three Perturbations: Comparing Protein Unfolding Under Shear, Force, and Thermal Stresses}, journal = {J Phys Chem B}, volume = {122}, year = {2018}, month = {Dec}, pages = {11922-11930}, abstract = {

The perturbation of a protein conformation by a physiological fluid flow is crucial in various biological processes including blood clotting and bacterial adhesion to human tissues. Investigating such mechanisms by computer simulations is thus of great interest, but it requires development of ad hoc strategies to mimic the complex hydrodynamic interactions acting on the protein from the surrounding flow. In this study, we apply the Lattice Boltzmann Molecular Dynamics (LBMD) technique built on the implicit solvent coarse-grained model for protein Optimized Potential for Efficient peptide structure Prediction (OPEP) and a mesoscopic representation of the fluid solvent, to simulate the unfolding of a small globular cold-shock protein in shear flow and to compare it to the unfolding mechanisms caused either by mechanical or thermal perturbations. We show that each perturbation probes a specific weakness of the protein and causes the disruption of the native fold along different unfolding pathways. Notably, the shear flow and the thermal unfolding exhibit very similar pathways, while because of the directionality of the perturbation, the unfolding under force is quite different. For force and thermal disruption of the native state, the coarse-grained simulations are compared to all-atom simulations in explicit solvent, showing an excellent agreement in the explored unfolding mechanisms. These findings encourage the use of LBMD based on the OPEP model to investigate how a flow can affect the function of larger proteins, for example, in catch-bond systems.

}, doi = {10.1021/acs.jpcb.8b08711}, author = {Languin-Catto{\"e}n, Olivier and Melchionna, Simone and Philippe Derreumaux and Guillaume Stirnemann and Sterpone, Fabio} } @article {2017|2029, title = {Multi-scale simulations of biological systems using the OPEP coarse-grained model.}, journal = {Biochem Biophys Res Commun}, year = {2017}, month = {2017 Sep 14}, abstract = {

Biomolecules are complex machines that are optimized by evolution to properly fulfill or contribute to a variety of biochemical tasks in the cellular environment. Computer simulations based on quantum mechanics and atomistic force fields have been proven to be a powerful microscope for obtaining valuable insights into many biological, physical, and chemical processes. Many interesting phenomena involve, however, a time scale and a number of degrees of freedom, notably if crowding is considered, that cannot be explored at an atomistic resolution. To bridge the gap between reality and simulation, many different advanced computational techniques and coarse-grained (CG) models have been developed. Here, we report some applications of the CG OPEP protein model to amyloid fibril formation, the response of catch-bond proteins to two types of fluid flow, and interactive simulations to fold peptides with well-defined 3D structures or with intrinsic disorder.

}, issn = {1090-2104}, doi = {10.1016/j.bbrc.2017.08.165}, author = {Sterpone, Fabio and Doutreligne, S{\'e}bastien and Tran, Thanh Thuy and Melchionna, Simone and Marc Baaden and Phuong Hoang Nguyen and Philippe Derreumaux} } @conference {2016|1607, title = {Hydrodynamic Effects on Amyloid-beta Aggregation}, booktitle = {Biophys. J.}, volume = {110}, number = {3, 1}, year = {2016}, note = {60th Annual Meeting of the Biophysical-Society, Los Angeles, CA, FEB 27-MAR 02, 2016}, month = {feb}, pages = {219A}, publisher = {Biophys Soc}, organization = {Biophys Soc}, issn = {0006-3495}, author = {Chiricotto, Mara and Melchionna, Simone and Philippe Derreumaux and Fabio Sterpone} } @article {2016|1702, title = {Hydrodynamic effects on beta-amyloid (16-22) peptide aggregation}, journal = {J. Chem. Phys.}, volume = {145}, number = {3}, year = {2016}, month = {jul}, abstract = {Computer simulations based on simplified representations are routinely used to explore the early steps of amyloid aggregation. However, when protein models with implicit solvent are employed, these simulations miss the effect of solvent induced correlations on the aggregation kinetics and lifetimes of metastable states. In this work, we apply the multi-scale Lattice Boltzmann Molecular Dynamics technique (LBMD) to investigate the initial aggregation phases of the amyloid A beta(16-22) peptide. LBMD includes naturally hydrodynamic interactions (HIs) via a kinetic on-lattice representation of the fluid kinetics. The peptides are represented by the flexible OPEP coarse-grained force field. First, we have tuned the essential parameters that control the coupling between the molecular and fluid evolutions in order to reproduce the experimental diffusivity of elementary species. The method is then deployed to investigate the effect of HIs on the aggregation of 100 and 1000 A beta(16-22) peptides. We show that HIs clearly impact the aggregation process and the fluctuations of the oligomer sizes by favouring the fusion and exchange dynamics of oligomers between aggregates. HIs also guide the growth of the leading largest cluster. For the 100 A beta(16-22) peptide system, the simulation of similar to 300 ns allowed us to observe the transition from ellipsoidal assemblies to an elongated and slightly twisted aggregate involving almost the totality of the peptides. For the 1000 A beta(16-22) peptides, a system of unprecedented size at quasi-atomistic resolution, we were able to explore a branched disordered fibril-like structure that has never been described by other computer simulations, but has been observed experimentally. Published by AIP Publishing.}, issn = {0021-9606}, doi = {10.1063/1.4958323}, author = {Chiricotto, Mara and Melchionna, Simone and Philippe Derreumaux and Fabio Sterpone} } @article {2016|1735, title = {Multiscale simulation of molecular processes in cellular environments}, journal = {Philosophical Transactions of the Royal Society A-mathematical Physical and Engineering Sciences}, volume = {374}, number = {2080}, year = {2016}, abstract = {We describe the recent advances in studying biological systems via multiscale simulations. Our scheme is based on a coarse-grained representation of the macromolecules and a mesoscopic description of the solvent. The dual technique handles particles, the aqueous solvent and their mutual exchange of forces resulting in a stable and accurate methodology allowing biosystems of unprecedented size to be simulated. This article is part of the themed issue {\textquoteleft}Multiscale modelling at the physics-chemistry-biology interface{\textquoteright}.}, issn = {1364-503X}, doi = {10.1098/rsta.2016.0225}, author = {Chiricotto, Mara and Fabio Sterpone and Philippe Derreumaux and Melchionna, Simone} } @conference {2016|1608, title = {Toward Microscopic Simulations of Proteins in Cell-Like Environments}, booktitle = {Biophys. J.}, volume = {110}, number = {3, 1}, year = {2016}, note = {60th Annual Meeting of the Biophysical-Society, Los Angeles, CA, FEB 27-MAR 02, 2016}, month = {feb}, pages = {386A}, publisher = {Biophys Soc}, organization = {Biophys Soc}, issn = {0006-3495}, author = {Fabio Sterpone and Philippe Derreumaux and Melchionna, Simone} } @article {2015|1634, title = {Amyloid beta Protein and Alzheimer{\textquoteright}s Disease: When Computer Simulations Complement Experimental Studies}, journal = {Chem. Rev.}, volume = {115}, number = {9}, year = {2015}, month = {may}, pages = {3518{\textendash}3563}, doi = {10.1021/cr500638n}, author = {Nasica-Labouze, Jessica and Phuong Hoang Nguyen and Fabio Sterpone and Berthoumieu, Olivia and Buchete, Nicolae-Viorel and Cote, Sebastien and De Simone, Alfonso and Doig, Andrew J. and Faller, Peter and Garcia, Angel and Laio, Alessandro and Li, Mai Suan and Melchionna, Simone and Mousseau, Normand and Mu, Yuguang and Paravastu, Anant and Pasquali, Samuela and Rosenman, David J. and Strodel, Birgit and Tarus, Bogdan and Viles, John H. and Zhang, Tong and Wang, Chunyu and Philippe Derreumaux} } @article {2015|1709, title = {Protein Simulations in Fluids: Coupling the OPEP Coarse-Grained Force Field with Hydrodynamics}, journal = {J. Chem. Theory Comput.}, volume = {11}, number = {4}, year = {2015}, month = {apr}, pages = {1843{\textendash}1853}, doi = {10.1021/ct501015h}, author = {Fabio Sterpone and Philippe Derreumaux and Melchionna, Simone} } @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} } @article {2013|1926, title = {How Conformational Flexibility Stabilizes the Hyperthermophilic Elongation Factor G-Domain}, journal = {J. Phys. Chem. B}, volume = {117}, number = {44}, year = {2013}, month = {nov}, pages = {13775{\textendash}13785}, author = {Kalimeri, Maria and Rahaman, Obaidur and Melchionna, Simone and Sterpone, Fabio} } @inbook {2013|1533, title = {Inquiring Protein Thermostability: Is Resistance to Temperature Stress a Rigidity/Flexibility Trade-off?}, booktitle = {Proceedings of the European Conference on Complex Systems 2012}, year = {2013}, publisher = {Springer International Publishing}, organization = {Springer International Publishing}, author = {Kalimeri, Maria and Melchionna, Simone and Sterpone, Fabio} } @article {2012|1795, title = {Thermophilic proteins: insight and perspective from in silico experiments}, journal = {Chem. Soc. Rev.}, volume = {41}, year = {2012}, pages = {1665{\textendash}1676}, publisher = {The Royal Society of Chemistry}, abstract = {Proteins from thermophilic and hyperthermophilic organisms are stable and function at high temperatures (50-100 [degree]C). The importance of understanding the microscopic mechanisms underlying this thermal resistance is twofold: it is key for acquiring general clues on how proteins maintain their fold stable and for targeting those medical and industrial applications that aim at designing enzymes that can work under harsh conditions. In this tutorial review we first provide the general background of protein thermostability by specifically focusing on the structural and thermodynamic peculiarities; next{,} we discuss how computational studies based on Molecular Dynamics simulations can broaden and refine our knowledge on such special class of proteins.}, author = {Sterpone, Fabio and Melchionna, Simone} } @article {2009|1831, title = {Key role of proximal water in regulating thermostable proteins}, journal = {J. Phys. Chem. B}, volume = {113}, number = {1}, year = {2009}, month = {jan}, pages = {131{\textendash}7}, abstract = {Three homologous proteins with mesophilic, thermophilic and hyperthermophilic character have been studied via molecular dynamics simulations at four different temperatures in order to investigate how water controls thermostability. The water-exposed surface of the protein is shown to increase with the degree of thermophilicity, and the role of water in enhancing the protein internal flexibility and structural robustness is elucidated. The presence of water-water hydrogen bond clusters enveloping the macromolecule is shown to correlate with thermal robustness when going from the mesophilic to the hyperthermophilic variants. Our analysis indicates that essential contributions to thermostability stem from protein-water surface effects whereas the protein internal packing plays a minor role.}, doi = {10.1021/jp805199c}, author = {Sterpone, Fabio and Bertonati, Claudia and Briganti, Giuseppe and Melchionna, Simone} }