Dynamic Cooperativity of Ligand-Residue Interactions Evaluated with the Fragment Molecular Orbital Method.

Abstract

By the splendid advance in computation power realized with the Fugaku supercomputer, it has become possible to perform ab initio fragment molecular orbital (FMO) calculations for thousands of dynamic structures of protein-ligand complexes in a parallel way. We thus carried out electron-correlated FMO calculations for a complex of the 3C-like (3CL) main protease (Mpro) of the new coronavirus (SARS-CoV-2) and its inhibitor N3 incorporating the structural fluctuations sampled by classical molecular dynamics (MD) simulation in hydrated conditions. Along with a statistical evaluation of the interfragment interaction energies (IFIEs) between the N3 ligand and the surrounding amino-acid residues for 1000 dynamic structure samples, in this study we applied a novel approach based on principal component analysis (PCA) and singular value decomposition (SVD) to the analysis of IFIE data in order to extract the dynamically cooperative interactions between the ligand and the residues. We found that the relative importance of each residue is modified via the structural fluctuations and that the ligand is bound in the pharmacophore in a dynamic manner through collective interactions formed by multiple residues, thus providing new insight into structure-based drug discovery.