Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.69091
Keywords
SARS-CoV-2 spike protein; single-molecule force spectroscopy; MD simulations; protein-protein interaction; None
Categories
Funding
- National Key Research and Development Program of China [2020YFA0509000]
- Fundamental Research Funds for the Central Universities [14380205]
- Natural Science Foundation of Jiangsu Province [BK20200058, BK20202004, BK20190275]
- National Natural Science Foundation of China [21771103, 21977047, 3217110056]
- Jiangsu Scientific and Technological Innovations Platform named Jiangsu Provincial Service Center for Antidiabetic Drug Screening
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Research indicates that the N501Y mutation in SARS-CoV-2 variants strengthens its interaction with ACE2, leading to an increased transmission rate, highlighting the need for close monitoring of future mutations in the virus' RBD.
SARS-CoV-2 has been spreading around the world for the past year. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Molecular dynamics simulations of RBD-ACE2 complexes indicated that the N501Y mutation introduced additional pi-pi and pi -cation interactions that could explain the changes observed by force microscopy. Taken together, these results suggest that the reinforced RBD-ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance.
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