A Coarse-Grained Protein−Protein Potential Derived from an All-Atom Force Field

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.