In order to study protein-protein nonbonded interactions, we present the development of a new reduced protein model that represents each amino acid residue with one to three coarse grains, whose physical properties are derived in a consistent bottom-up procedure from the higher-resolution all-atom AMBER force field. The resulting potential energy function is pairwise additive and includes distinct van-der-Waals and Coulombic terms. The van-der-Waals effective interactions are deduced from preliminary molecular dynamics simulations of all possible amino acid homodimers. They are best represented by a soft 1/r6 repulsion and a Gaussian attraction, with parameters obeying Lorentz-Berthelot mixing rules. For the Coulombic interaction, coarse grain charges are optimized for each separate protein in order to best represent the all-atom electrostatic potential outside the protein core. This approach leaves the possibility of using any implicit solvent model to describe solvation effects and electrostatic screening. The coarse-grained force field is tested carefully for a small homodimeric complex, the magainin. It is shown to reproduce satisfactorily the specificity of the all-atom underlying potential, in particular within a PB/SA solvation model. The coarse-grained potential is applied to the redocking prediction of three different protein-protein complexes: the magainin dimer, the barnase-barstar, and the trypsin-BPTI complexes. It is shown to provide per se an efficient and discriminating scoring energy function for the protein-protein docking problem that remains pertinent at both the global and refinement stage.

Like other protein-protein interaction domains, PDZ domains are involved in many key cellular processes. These processes often require that specific multiprotein complexes be assembled, a task that PDZ domains accomplish by binding to specific peptide motifs in target proteins. However, a growing number of experimental studies show that PDZ domains (like other protein-protein interaction domains) can engage in a variety of interactions and bind distinct peptide motifs. Such promiscuity in ligand recognition raises intriguing questions about the molecular and thermodynamic mechanisms that can sustain it. To identify possible sources of promiscuity and selectivity underlying PDZ domain interactions, we performed molecular dynamics simulations of 20 to 25 ns on a set of 12 different PDZ domain complexes (for the proteins PSD-95, Syntenin, Erbin, GRIP, NHERF, Inad, Dishevelled, and Shank). The electrostatic, nonpolar, and configurational entropy binding contributions were evaluated using the MM/PBSA method combined with a quasi-harmonic analysis. The results revealed that PDZ domain interactions are characterized by overwhelmingly favorable nonpolar contributions and almost negligible electrostatic components, a mix that may readily sustain promiscuity. In addition, despite the structural similarity in fold and in recognition modes, the entropic and other dynamical aspects of binding were remarkably variable not only across PDZ domains but also for the same PDZ domain bound to distinct ligands. This variability suggests that entropic and dynamical components can play a role in determining selectivity either of PDZ domain interactions with peptide ligands or of PDZ domain complexes with downstream effectors.

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.