![]() ![]() ![]() As of December 2020, more than 80 million cases have been reported worldwide, with more than 1.7 million deaths ( ). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, single stranded, enveloped RNA virus that belongs to the Coronaviridae family and is the causative agent of the COVID-19 pandemic. By elucidating a mechanistic basis for the increased affinity of the N501Y mutation in S1-RBD for ACE2, we believe that the results presented here will aid in developing therapeutic strategies against SARS-CoV-2 including designing drugs targeting the ACE2-S1-RBD interaction. Additionally, we find that the N501Y mutant S1-RBD displays altered dynamics that likely aids in its enhanced interaction with ACE2. Here, we dissect the mechanism underlying the increased affinity using molecular dynamics (MD) simulations of the available ACE2-S1-RBD complex structure (6M0J) and show a prolonged and stable interaction of the Y501 residue in the N501Y mutant S1-RBD with interfacial residues, Y41 and K353, in ACE2 as compared to the wild type S1-RBD. Specifically, the N501Y mutation in the SARS-CoV-2 S1 receptor binding domain (RBD) domain has been shown to possess increased affinity for ACE2, although the basis for this not yet clear. In this regard, the latest SARS-CoV-2 variant, B.1.1.7 lineage, reported from the United Kingdom (UK) is of great significance, in that it contains several mutations that increases its infection and transmission rates as evidenced by the increased number of clinical reports. COVID-19 caused by SARS-CoV-2 has caused a massive health crisis across the world, and genetic variants such as the D614G gaining enhanced infectivity and competitive fitness have significantly aggravated the global concern. ![]()
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