Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants

Abstract

The emergence of a variety of highly transmissible SARS-CoV-2 variants, the causative agent of COVID-19, with multiple spike mutations poses serious challenges in overcoming the ongoing deadly pandemic. It is, therefore, essential to understand how these variants gain enhanced ability to evade immune responses with a higher rate of spreading infection. To address this question, here we have individually assessed the effects of SARS-CoV-2 variant-specific spike (S) protein receptor-binding domain (RBD) mutations E484K, K417N, L452Q, L452R, N501Y, and T478K that characterize and differentiate several emerging variants. Despite the hundreds of apparently neutral mutations observed in the domains other than the RBD, we have shown that each RBD mutation site is differentially engaged in an interdomain allosteric network involving mutation sites from a distant domain, affecting interactions with the human receptor angiotensin-converting enzyme-2 (ACE2). This allosteric network couples the residues of the N-terminal domain (NTD) and the RBD, which are modulated by the RBD-specific mutations and are capable of propagating mutation-induced perturbations between these domains through a combination of structural changes and effector-dependent modulations of dynamics. One key feature of this network is the inclusion of compensatory mutations segregated into three characteristically different clusters, where each cluster residue site is allosterically coupled with specific RBD mutation sites. Notably, each RBD mutation acted like a positive allosteric modulator; nevertheless, K417N was shown to have the largest effects among all of the mutations on the allostery and thereby holds the highest binding affinity with ACE2. This result will be useful for designing the targeted control measure and therapeutic efforts aiming at allosteric modulators.