Molecular Mechanism of the N501Y Mutation for Enhanced Binding between SARS-CoV-2’s Spike Protein and Human ACE2 Receptor

Coronavirus disease 2019 (COVID-19) has been an ongoing global pandemic for over a year. Recently, an emergent SARS-CoV-2 variant (B.1.1.7) with an unusually large number of mutations had become highly contagious and wide-spreading in United Kingdom. From genome analysis, the N501Y mutation within the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein might have enhanced the viral protein’s binding with the human angiotensin converting enzyme 2 (hACE2). The latter is the prelude for the virus’ entry into host cells. So far, the molecular mechanism of this enhanced binding is still elusive, which prevents us from assessing its effects on existing therapeutic antibodies. Using all atom molecular dynamics simulations, we demonstrated that Y501 in mutated RBD can be well coordinated by Y41 and K353 in hACE2 through hydrophobic interactions, increasing the overall binding affinity between RBD and hACE2 by about 0.81 kcal/mol. We further explored how the N501Y mutation might affect the binding between a neutralizing antibody (CB6) and RBD. We expect that our work can help researchers design proper measures responding to this urgent virus mutation, such as adding a modified/new neutralizing antibody specifically targeting at this variant in the therapeutic antibody cocktail.