The Point Mutations in SARS-CoV-2 Variants Induce Long-Range Dynamical Perturbations in Neutralizing Antibodies

Abstract

AbstractMonoclonal antibodies are emerging as a viable treatment for COVID-19. However, new SARS-CoV-2 variants can reduce the efficacy of currently available antibodies and can diminish vaccine-induced immunity. Here, we demonstrate that the molecular dynamics of neutralizing monoclonal antibodies can be profoundly modified by the amino-acid mutations present in the spike proteins of the SARS-COV-2 variants currently circulating in the world population. The dynamical perturbations within the antibody structure, which can alter the thermodynamics of antigen-antibody binding, are found to be diverse and to depend both on the nature of the antibody and on the spatial location of the spike mutation. The correlation between the motion of the antibody and that of the spike receptor binding domain (RBD) can also be changed, and this, in turn, can additionally modify the binding affinity. Using protein graph connectivity networks, we delineated the mutant-induced modifications in the information-flow along the allosteric pathway throughout the antibody. Changes in the collective dynamics were spatially distributed both locally and across long-range distances within the antibody. On the receptor side, we identified an anchor-like structural element that prevents the detachment of the antibodies; individual mutations there can significantly affect the antibody binding propensity. Our study provides insight into how virus neutralization by monoclonal antibodies can be impacted by local mutations in the epitope via a dynamical standpoint. This realization adds a new layer of sophistication to be included in the efforts to rationally design monoclonal antibodies effective against new variants of SARS-CoV2 that take allostery in the antibody in consideration.