Enhanced binding of the N501Y-mutated SARS-CoV-2 spike protein to the human ACE2 receptor: insights from molecular dynamics simulations.

Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (B.1.1.7 and B.1351) have emerged harbouring mutations that make them highly contagious. The N501Y mutation within the receptor-binding domain (RBD) of the spike protein of these SARS-CoV-2 variants may enhance binding to the human angiotensin-converting enzyme 2 (hACE2). However, no molecular explanation for such an enhanced affinity has so far been provided. Here, using all-atom molecular dynamics simulations, we show that Y501 in the mutated RBD can be well-coordinated by Y41 and K353 in hACE2 through hydrophobic interactions, which may increase the overall binding affinity of the RBD for hACE2 by approximately 0.81 kcal·mol-1 . The binding dynamics revealed in our study may provide a working model to facilitate the design of more effective antibodies.