On the in silico application of the center-of-mass distance method

Abstract

This study aims to protocolize the utilization of the center-of-mass (CoM) distance method in GROMACS MD simulation software as a useful method for evaluating the binding affinity change in heterodimeric protein due to induced changes in one of the units. The hypothesis underlines the basic principles in biophysics, that an increase of the binding affinity is expected to reduce the relative CoM distance between monomers, while the opposite is expected to increase the relative CoM distance. However, it has been found that the CoM distance analysis must be strictly preformed during the convergent phase of systems’ dynamics, once the monomers enter mutually stable conformation — a limitation which has usually been overlooked. The method was used to study the impact of K417Y severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface glycoprotein (S-protein) mutation. It has been found that the K417Y mutation favors reduced binding affinity between SARS-CoV-2 S-protein and human angiotensin-converting enzyme 2 (hACE2) receptor, which is due to the loss of the permanent K417-D30 salt bridge in favor of a temporary Y417-D30 hydrogen bond. The destabilizing impact of K417Y mutation on S-protein–hACE2 complex was confirmed by radius of gyration analysis.