Coarse-grained model for simulating protein complexes: Folded vs. disordered proteins.

Abstract

We develop a residue-level coarse-grained model for simulating multi-protein complexes. Contact potentials and distances between all pairs of residues are constructed via Boltzmann inversion of inter-molecular contacts of more than 22000 non-redundant unique interfaces of protein complexes. We show that the contact potentials between hydrophobic pairs are less sensitive to the residue identities when compared to the Miyazawa-Jernigan contact potentials derived from intra-molecular contacts. On the other hand, the contact potentials between hydrophilic pairs depend more strongly on the residue identities. These potentials and contact distances are adopted to the modified Wang-Frenkel potential for the short-range van der Waals (vdW) interactions and Deybe-Hückel electrostatics with a distance-dependent dielectric constant to simulate thermodynamic, kinetic, and structural properties of protein complexes of folded and disordered proteins. Upon parameterizing to fit the second virial coefficient of lysozyme and the binding affinities of the ubiquitin and ubiquitin-binding domains, we show that the potential form with a shorter cutoff distance performs best in predicting the binding affinities and structures for folded proteins. On the other hand, the structural properties of disordered proteins measured by the radius of gyration are in better agreement with experimental data at longer cutoff distances. Comparison between pairwise contact distributions for folded and disordered proteins shows that contacts between charged and polar residues are more prevalent in disordered proteins. The potentials are modified to account for this disparity. We show that the modified potentials perform well in predicting the binding affinities and structures for folded proteins as well as the radius of gyration for disordered proteins. The model can easily be implemented to many existing simulation packages to simulate multi-protein complexes containing disordered regions or proteins in order to gain insights into understanding many biological processes inside a cell.