Un modèle de solvatation semi-implicite pour la simulation des macromolécules biologiques

Dans la cellule des organismes vivants, le solvant (l'eau) joue un rôle très important dans la stabilisation des structures tridimensionnellles des macromolécules biologiques et lors de leurs interactions. Les méthodes théoriques de simulations de modélisation moléculaire permettent de compléter les informations partielles sur l'hydratation des biomolécules obtenues par les méthodes expérimentales. Nous avons développé un nouveau modèle de solvatation semi-implicite pour représenter le solvant en modélisation moléculaire. Ce modèle décrit le solvant comme des particules microscopiques dont les propriétés diéléctriques découlent des lois macroscopiques de l'électrostatique. Nous obtenons ainsi à l'équilibre électrostatique un fluide de paticules de Lennard-Jones non polaires, polarisables par le champ électrique crée par le soluté. Ce modèle a l'intérêt de prendre en compte la structure moléculaire du solvant tout en calculant efficacement l'énergie libre électrostatique de solvatation du système. De plus, il est d'un faible coût numérique comparé aux méthodes explicites. Après avoir implémenté notre modèle dans un programme de dynamique moléculaire et l'avoir paramétré de façon simple, nous l'avons appliqué à plusieurs peptides, protéines et acides nucléiques (ADN et ARN de transfert). Les trajectoires de ces simulations sont stables sur une à deux nanosecondes, et les structures obtenues sont tout à fait en accord avec les modèles expérimentales et les méthodes théoriques de solvatation explicites. Notre modèle permet également de retrouver les sites préférentiels d'hydratation des molécules étudiées identifiés expérimentalement ou théoriquement, malgré l'absence de liaisons hydrogène dans notre solvant. De plus, nous observons de bonnes corrélation entre les énergies libres électrostatiques de solvatation calculées avec notre modèle et celles calculées avec les méthodes de résolution de l'équation de Poisson-Boltzmann, et ces résultats paraissent très encourageants.EVRY-BU (912282101) / SudocSudocFranceF

Structure et dynamique moléculaire de la protéine FtsZ

FtsZ est une protéine indispensable à la multiplication bactérienne. Elle est une cible thérapeutique intéressante dans la recherche de nouvelles molécules antibiotiques. FtsZ se polymérise en filaments qui s'assemblent en une structure : le "Z-ring". FtsZ est une GTPase qui lie et hydrolyse le GTP, pour donner un GDP. L'objectif de cette thèse est d'étudier par dynamique moléculaire l'influence du nucléotide GTP/GDPet de l'ion Mg2+ sur les changements conformationnels ainsi que sur la dynamique de FtsZ. Une première approche a consisté à étudier le monomère de FtsZ. Ces simulations n'ont révélé que peu d'influence de la nature du nucléotide sur la structure. Cependant, la présence de l'ion Mg2+ dans la poche du nucléotide provoque des changements conformationnels de FtsZ-GDP ainsi qu'un mouvement du GDP au sein du site actif. Dans la deuxième partie, l'étude du dimère de FtsZ a permis d'explorer en plus de l'influence du nucléotide, celle de l'état de protonation des chaînes latérales de trois acides aspartiques (Asp72A, Asp235B et Asp238B) présents à l'interface. Les résultats ont démontré que les chaînes latérales des Asp235B et 238B doivent être protonées pour que le dimère FtsZ-GTP-Mg soit stable. D'autre part, dans le dimère FtsZ-GDP-Mg en solution, la protonation des Asp 235B et 238B provoque une courbure du dimère avec un éloignement des monomères et un déplacement du GDP à l'interface. Cette séparation ressemble à un début de dépolymérisation. le GDP et l'ion Mg2+ provoquent des déformations du monomère et du dimère de FtsZ. Une étude approfondie de la protonation des résidus de l'interface permettrait de mieux comprendre la polymérisation et l'hydrolyse du GTP.Most bacteria use a prokaryotic protein, FtsZ to divide. FtsZ polymerizes and assembles into the "Z-ring". FtsZ is a GTPase that can bind and hydrolyze GTP. The aim of this study is to explore FtsZ structure and dynamics as a function of GTP/GDP. First, we performed molecular dynamics simulations of FtsZ monomer to study the influence of GTP/GDP and Mg2+ ion on its structure and dynamics. These simulations revealed that the nature of the nucleotide doesn't affect the structure of FtsZ. However, the presence of the magnesium ion in the nucleotide-binding pocket causes conformational changes of FtsZ monomer when bound to GDP. The Mg2+ ion induces a dynamical motion of the GDP within the nucleotide-binding site. In the second part, we studied the influence of the nucleotide on FtsZ dimer by molecular dynamics. These simulations also allowed to investigate the influence of the protonation state of three aspartic acids sidechains (Asp72A, Asp235B and Asp238B). These Asp are present at the dimer interface. We demonstrated that the sidechains of two aspartic acids Asp235B and Asp238B have to be protonated during polymerization of FtsZ-GTP-Mg dimer. On the other hand, when the sidechains of Asp235B and Asp238B are protonated, FtsZ-GDP-Mg dimer gets curved and the two monomers are separated. We also observed a GDP motion at the dimer interface. This separation looks like the beginning of depolymerization. The association of GDP with the Mg2+ ion causes important conformational changes of FtsZ monomer and dimer. An in-depth study of the protonation state of residues at the interface would allow a better understanding of polymerization of FtsZ and GTP hydrolysis.EVRY-Bib. électronique (912289901) / SudocSudocFranceF

Modeling Protein–Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION

International audienceWe present here the SCORPION - Solvated COaRse-grained Protein interactION - force field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein-protein recognition in a solvated environment

Influence of GTP/GDP and magnesium ion on the solvated structure of the protein FtsZ: a molecular dynamics study

International audienceWe present here a structural analysis of ten extensive all-atom molecular dynamics simulations of the monomeric protein FtsZ in various binding states. Since the polymerization and GTPase activities of FtsZ depend on the nature of a bound nucleotide as well as on the presence of a magnesium ion, we studied the structural differences between the average conformations of the following five systems: FtsZ-Apo, FtsZ-GTP, FtsZ-GDP, FtsZ-GTP-Mg, and FtsZ-GDP-Mg. The in silico solvated average structure of FtsZ-Apo significantly differs from the crystallographic structure 1W59 of FtsZ which was crystallized in a dimeric form without nucleotide and magnesium. The simulated Apo form of the protein also clearly differs from the FtsZ structures when it is bound to its ligand, the most important discrepancies being located in the loops surrounding the nucleotide binding pocket. The three average structures of FtsZ-GTP, FtsZ-GDP, and FtsZ-GTP-Mg are overall similar, except for the loop T7 located at the opposite side of the binding pocket and whose conformation in FtsZ-GDP notably differs from the one in FtsZ-GTP and FtsZ-GTP-Mg. The presence of a magnesium ion in the binding pocket has no impact on the FtsZ conformation when it is bound to GTP. In contrast, when the protein is bound to GDP, the divalent cation causes a translation of the nucleotide outwards the pocket, inducing a significant conformational change of the loop H6-H7 and the top of helix H7

Modeling Protein–Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION

We present here the SCORPIONSolvated COaRse-grained Protein interactIONforce field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein–protein recognition in a solvated environment

Modeling Protein–Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION

We present here the SCORPIONSolvated COaRse-grained Protein interactIONforce field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein–protein recognition in a solvated environment

Modeling Protein–Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION

We present here the SCORPIONSolvated COaRse-grained Protein interactIONforce field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein–protein recognition in a solvated environment

Modeling Protein–Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION

We present here the SCORPIONSolvated COaRse-grained Protein interactIONforce field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein–protein recognition in a solvated environment

Modeling Protein–Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION

We present here the SCORPIONSolvated COaRse-grained Protein interactIONforce field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein–protein recognition in a solvated environment

Modeling Protein–Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION

We present here the SCORPIONSolvated COaRse-grained Protein interactIONforce field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein–protein recognition in a solvated environment