Enhanced binding of the N501Y-mutated SARS-CoV-2 spike protein to the human ACE2 receptor: insights from molecular dynamics simulations

Abstract

Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (B.1.1.7 and B.1351) have emerged harbouring mutations that make them highly contagious. The N501Y mutation within the receptor-binding domain (RBD) of the spike protein of these SARS-CoV-2 variants may enhance binding to the human angiotensin-converting enzyme 2 (hACE2). However, no molecular explanation for such an enhanced affinity has so far been provided. Here, using all-atom molecular dynamics simulations, we show that Y501 in the mutated RBD can be well-coordinated by Y41 and K353 in hACE2 through hydrophobic interactions, which may increase the overall binding affinity of the RBD for hACE2 by approximately 0.81 kcal·mol^-1 . The binding dynamics revealed in our study may provide a working model to facilitate the design of more effective antibodies.

Keywords: ACE2; N501Y; SARS-CoV-2; antibody; spike protein.

Fig. 1

MD simulation of the hACE2‐sRBD complex. (A) Cartoon illustration of hACE2 (orange) bound with sRBD (gray). The residue N501 on sRBD is in the van der Waals sphere representation. Na⁺ and Cl⁻ are shown as tan and cyan balls, respectively, and, for clarity, water is not shown. (B) RMSFs for residues in sRBD in MD simulation. (C) Time‐dependent interfacial contact areas between hACE2 and sRBD. (D) Equilibrated atomic structure for N501 in sRBD coordinating with Y41 and K353 in hACE2.

Fig. 2

Illustration of a thermodynamic cycle used in the FEP calculations with the mutation N501Y. (A) The bound state between the original sRBD and hACE2. (B) The bound state between the mutated sRBD (N501Y) and hACE2. (C) The free state of the original sRBD (with N501) in water. (D) The free state of the mutated sRBD (with Y501) in water. Protein segments (in cartoon representation) are colored the same as those in Fig. 1A.

Fig. 3

Enhanced interfacial coordinations between Y501 in sRBD and key residues (Y41 and K353) in hACE2.

Fig. 4

Effects of the N501Y mutation on the binding between the neutralizing mAb CB6 and sRBD. (A) The complex of sRBD and the Fab (in CB6) equilibrated in MD simulation. The Fab comprises one heavy chain (fragment) and one light chain, colored in blue and orange respectively; the sRBD is in gray. The heavy (light) chain contains a variable region V^H (V^L) and a constant region C^H (C^L). (B) Coordinations between N501 in sRBD and its surrounding residues (S30, R31 and Y32) in Fab, at the beginning of the FEP calculation. (C) Coordinations between Y501 in sRBD and surrounding residues (S30, R31 and Y32) in Fab, at the end of the FEP calculation.