Atomic force microscopy

Force spectroscopy

Pathology

Receptor

Nanotechnology

Disease

Coronavirus disease 2019 (COVID-19)

Infectious disease (medical specialty)

Biology

Gene

Binding site

Biophysics

Computational chemistry

Chemistry

Materials science

Mutation

Molecular dynamics

Cell biology

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Plasma protein binding

Genetics

Medicine

Mutation rate

eLife

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 π-π and π-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.

N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2