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The wide spread of coronavirus disease 2019 (COVID-19) has declared a globalhealth emergency. As one of the most important targets for antibody and drugdevelopments, Spike RBD-ACE2 interface has received extensive attention. Here,using molecular dynamics simulations, we explicitly evaluated the bindingenergetic features of the RBD-ACE2 complex of both SARS-CoV and SARS-CoV-2 tofind the key residues. Although the overall ACE2-binding mode of the SARS-CoV-2RBD is nearly identical to that of the SARS-CoV RBD, the difference in bindingaffinity is as large as -16.35 kcal/mol. Energy decomposition analysesidentified three binding patches in the SARS-CoV-2 RBD and eleven key residues(Phe486, Tyr505, Asn501, Tyr489, Gln493, Leu455 and etc) which are believed tobe the main targets for drug development. The dominating forces are from vander Waals attractions and dehydration of these residues. It is also worthmention that we found seven mutational sites (Lys417, Leu455, Ala475, Gly476,Glu484, Gln498 and Val503) on SARS-CoV-2 which unexpectedly weakened theRBD-ACE2 binding. Very interestingly, the most repulsive residue at theRBD-ACE2 interface (E484), is found to be mutated in the latest UK variant,B1.1.7, cause complete virus neutralization escapes from highly neutralizingCOVID-19 convalescent plasma. Our present results indicate that at least fromthe energetic point of view such E484 mutation may have beneficial effects onACE2 binding. The present study provides a systematical understanding, from theenergetic point of view, of the binding features of SARS-CoV-2 RBD with ACE2acceptor. We hope that the present findings of three binding patches, keyattracting residues and unexpected mutational sites can provide insights to thedesign of SARS-CoV-2 drugs and identification of cross-active antibodies.

Quantitative Interpretations of Energetic Features and Key Residues at SARS Coronavirus Spike Receptor-Binding Domain and ACE2 Receptor Interface