ABSTRACT
Multiple SARS-CoV-2 variants have widely spread around the globe since the end of 2020, all carrying the common N501Y mutation at the receptor binding motif of the viral-surface spike protein. Experimental studies show that N501Y enhances viral binding to human angiotensin converting enzyme 2 (ACE2) and confers moderate resistance to certain monoclonal antibodies (mAbs). A mechanistic understanding of this mutation remains elusive. In this study, we used molecular dynamics simulation and alchemical free energy calculations, to systematically evaluate the effects of this prominent substitution on recognizing the host receptor ACE2 and different types of neutralizing mAbs. Our results suggest that this mutation alters the delicate local interaction with its binding partners: Y501 enhances local hydrophobicity, strengthens interaction with neighbouring K353 and Y41, and yields a Delta Delta G(binding) value of about -0.9 kcal mol(-1) to human ACE2, in quantitative agreement with the experimental measurement. Yet, N501Y diminishes the binding to cat ACE2 due to steric clash, indicating distinct transmissibility in different species. Meanwhile, the bulky Y501 reduces the binding to the antibody CB6 by about 4 folds, confirming recent experimental results. Intriguingly, the N501Y substitution fuses a larger hydrophobic core and sensitizes the binding to H014, which makes the viral strain more vulnerable to this typical antibody. The present study portraits the chemical nature of protein-protein interaction due to the SARS-CoV-2 spike protein mutation at atomic resolution and enlightens future investigations of other variants and vaccine design.