Computational Prediction of Mutational Effects on SARS-CoV‑2 Binding by Relative Free Energy Calculations

The
ability of coronaviruses to infect humans is invariably associated
with their binding strengths to human receptor proteins. Both SARS-CoV-2,
initially named 2019-nCoV, and SARS-CoV were reported to utilize angiotensin-converting
enzyme 2 (ACE2) as an entry receptor in human cells. To better understand
the interplay between SARS-CoV-2 and ACE2, we performed computational
alanine scanning mutagenesis on the “hotspot” residues
at protein–protein interfaces using relative free energy calculations.
Our data suggest that the mutations in SARS-CoV-2 lead to a greater
binding affinity relative to SARS-CoV. In addition, our free energy
calculations provide insight into the infectious ability of viruses
on a physical basis and also provide useful information for the design
of antiviral drugs.