Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human cells upon binding of its spike (S) glycoproteins to ACE2 receptors. Several nanobodies neutralize SARS-CoV-2 infection by binding to the receptor-binding domain (RBD) of S protein, but the underlying mechanism is not well understood. Here, we performed all-atom molecular dynamics simulations of nanobodies H11-H4, H11-D4, and Ty1 in complex with S protein and identified an extended network of pairwise interactions between RBD and these nanobodies. Our <i>in silico</i> pulling simulations performed at pulling speeds comparable to atomic force spectroscopy, showed that H11-H4 binds stronger to the WT S protein than ACE2, H11-D4 and Ty1. Although H11-H4 did not sterically overlap with ACE2, its binding to RBD resulted in dissociation of the S protein-ACE2 complexes due to electrostatic repulsion. To test whether these nanobodies can neutralize novel SARS-CoV-2 501Y.V1 and 501.V2 variants, we repeated the analysis performed for the WT. While both SARS-CoV-2 mutations showed negligible effect on ACE2 binding strength to S protein, N501Y/E484K/K417N (501.V2 variant) weakened H11-H4 and H11-D4 but strengthened Ty1 binding, suggesting that Ty1 is more effective against SARS-COV-2 501.V2 variant.

Exploring the binding mechanisms of nanobodies targeting SARS-CoV-2 spike glycoprotein using molecular dynamics simulations

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.