Investigation on the interaction mechanism of different SARS-CoV-2 spike variants with hACE2: insights from molecular dynamics simulations.

Since the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), SARS-CoV-2 has evolved by acquiring genomic mutations, resulting in the recent emergence of several SARS-CoV-2 variants with improved transmissibility and infectivity relative to the original strain. An underlying mechanism may be the increased ability of the mutants to bind the receptor proteins and infect the host cell. In this work, we implemented all-atom molecular dynamics (MD) simulations to study the binding and interaction of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein singly (D614G), doubly (D614G + L452R and D614G + N501Y), triply (D614G + N501Y + E484K), and quadruply (D614G + N501Y + E484K + K417T) mutated variants with the human angiotensin-converting enzyme 2 (hACE2) receptor protein in the host cell. A combination of multiple analysis approaches elucidated the effects of mutations and the extent of molecular divergence from multiple perspectives, including the dynamic correlated motions, interaction patterns, dominant motions, free energy landscape, and charge distribution on the electrostatic potential surface between the hACE2 and all RBD variants. Moreover, free energy calculations using the MM/PBSA method evaluated the binding affinity between these RBD variants and hACE2. The results showed that the D614G + N501Y + E484K variant possessed the lowest free energy value (highest affinity) compared to the D614G + N501Y + E484K + K417T, D614G + L452R, D614G + N501Y, and D614G mutants. The residue-based energy decomposition also indicated that the energy contribution of residues at the mutation site to the total binding energy was highly variable. The interaction mechanisms between the different RBD variants and hACE2 elucidated in this study will provide some insights into the development of drugs targeting the new SARS-CoV-2 variants.