Tap Ha-Duong

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.

Particle-Based Implicit Solvent Model for Biosimulations: Application to Proteins and Nucleic Acids Hydration

In addition to the simulation of two proteins described previously, we report on the application of our recently developed particle-based implicit solvent model to the simulations of four nucleic acid molecules, the 17 bases anticodon hairpin of the Asp-tRNA, the decamer d(CCGCCGGCGG) in both A and B form, and the containing EcoRI restriction site dodecamer d(CGCGAATTCGCG). The solvent is represented by a fluid of Lennard-Jones polarizable pseudoparticles of molecular size, the induced dipoles of which are sensitive to the solute electric field but not to each other. When implemented in a molecular dynamics algorithm with the Amber94 force field, the model allows to simulate efficiently the conformational evolution of the nucleic acids, yielding stable three-dimensional structures in agreement with experiments and other simulations in explicit solvent. In the same run, it is also able to provide estimations of the electrostatic solvation free energy within short time windows which correlate well with the Poisson-Boltzmann calculations. In addition, the molecular aspect of the solvent model allows for the reproduction of the highly localized water molecules in the major or minor grooves of the nucleic acid double helices, despite the absence of explicit water hydrogen bonds.

Protein Backbone Dynamics Simulations Using Coarse-Grained Bonded Potentials and Simplified Hydrogen Bonds

A new set of bonded potentials is introduced to model the flexibility of coarse-grained polypeptide chains. Based on a statistical analysis of known structures, the bonded potentials are sequence-dependent, and the secondary-structure propensity of each amino acid is partially reflected in the Si-Bi-Bi+1-Bi+2 pseudotorsion angle, where Si and Bi denote the side-chain and backbone beads, respectively. To stabilize the secondary structures during simulations, the bonded force field must be balanced by a simplified model of the protein hydrogen bonds, based on dipole-dipole interactions. Tested on eight polypeptides with sequence lengths ranging from 17 to 98, using 200-ns molecular dynamics simulations, the coarse-grained model yields trajectories with RMSDs ranging from 3 to 8 Å from the experimental conformations. The less-structured regions of the simulated proteins exhibit the largest-amplitude movements.

A semi‐implicit solvent model for the simulation of peptides and proteins

We present a new model of biomolecules hydration based on macroscopic electrostatic theory, that can both describe the microscopic details of solvent–solute interactions and allow for an efficient evaluation of the electrostatic hydration free energy. This semi‐implicit model considers the solvent as an ensemble of polarizable pseudoparticles whose induced dipole describe both the electronic and orientational solvent polarization. In the presented version of the model, there is no mutual dipolar interaction between the particles, and they only interact through short‐ranged Lennard–Jones interactions. The model has been integrated into a molecular dynamics code, and offers the possibility to simulate efficiently the conformational evolution of biomolecules. It is able to provide estimations of the electrostatic solvation free energy within short time windows during the simulation. It has been applied to the study of two small peptides, the octaalanine and the N‐terminal helix of ribonuclease A, and two proteins, the bovine pancreatic trypsin inhibitor and the B1 immunoglobin‐binding domain of streptococcal protein G. Molecular dynamics simulations of these biomolecules, using a slightly modified Amber force field, provide stable and meaningful trajectories in overall agreement with experiments and all‐atom simulations. Correlations with respect to Poisson–Boltzmann electrostatic solvation free energies are also presented to discuss the parameterization of the model and its consequences.

Dielectric constant of a highly polarizable atomic fluid: the clausius–mossotti versus the onsager relation

The relation between the dielectric constant and the particle polarizability for a polarizable liquid composed of Lennard-Jones particles carrying a saturable induced dipole is studied by computer simulations. It is shown that the widely accepted Clausius–Mossotti relation is only valid for low polarizabilities and fails for high polarizabilities. The results can be fitted accurately by an Onsager-like relation using an effective particle radius measured in the simulations which is larger than the equivalent hard-sphere radius defined conventionally. Furthermore, the orientational ordering transition found at high polarizabilities is shown to be of anti-ferroelectric type.

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

We 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.

Coarse-Grained Models of the Proteins Backbone Conformational Dynamics

Coarse-grained models are more and more frequently used in the studies of the proteins structural and dynamic properties, since the reduced number of degrees of freedom allows to enhance the conformational space exploration. This chapter attempts to provide an overview of the various coarse-grained models that were applied to study the functional conformational changes of the polypeptides main chain around their native state. It will more specifically discuss the methods used to represent the protein backbone flexibility and to account for the physico-chemical interactions that stabilize the secondary structure elements.

A Particle Based Implicit Solvent Model for Biomolecular Simulations

We present a recently developed alternative solvent model for biomolecules simulations that combine advantages of both explicit models (molecular aspect of water for structural informations) and implicit approaches (efficient and rapid calculation of solvation free energies). This model, named Polarizable Pseudo‐Particles (PPP), allows stable molecular dynamics simulations in the nanosecond range and yields free energies in good correlation with Poisson‐Boltzmann calculations.