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.

Energetics of Spike Protein Opening of SARS-CoV-1 and SARS-CoV-2 and Its Variants of Concern: Implications in Host Receptor Scanning and Transmission

“…In the context of currently circulating SARS-CoV-2 variants, mutations occurring outside the RBM region can modulate S protein opening directly or through long range allosteric networks. , The SARS-CoV-2 VOCs: alpha (B.1.1.7, beta (B.1.351), gamma (P.1), delta (B.1.617.2), and omicron (B.1.1.529) are associated with enhanced transmissibility and evasion from antibodies induced by natural infection or vaccination, compared to the ancestral or B.1 (D614G) variant. ,,, The higher transmission of the B.1 variant was attributed to D614G mutation which increases viral spike density and infectivity compared to ancestral SARS-CoV-2 . In SARS-CoV-2 VOCs, mutations in the RBM additionally contribute to ACE2 binding and thus higher transmission potential.…”

Riding the Wave: Unveiling the Conformational Waves from RBD of SARS-CoV-2 Spike Protein to ACE2

“…A greater loss of secondary structure was observed in the C-terminal region of the RBD, with multiple minima spread across the principal components, as shown in Figure q. The double mutations L452R and E484Q (kappa) could potentially have higher transmissibility, severity, or reinfection risk and require continuous monitoring. , Kappa mutations are highly contagious and can evade neutralizing antibodies . The free-energy landscape of the kappa variant exhibited a wide peak with the lowest energy and a single spike, as shown in Figure i.…”

“…The double mutations L452R and E484Q (kappa) could potentially have higher transmissibility, severity, or reinfection risk and require continuous monitoring. 64,65 Kappa mutations are highly contagious and can evade neutralizing antibodies. 64 The free-energy landscape of the kappa variant exhibited a wide peak with the lowest energy and a single spike, as shown in Figure 1i.…”

Interface design of SARS-CoV-2 symmetrical nsp7 dimer and machine learning-guided nsp7 sequence prediction reveals physicochemical properties and hotspots for nsp7 stability, adaptation, and therapeutic design

“…10 These variants mostly emerged from mutations in the intracellular proteins of SARS-CoV-2, and to fully grasp the impact of these variants, it is crucial to investigate the molecular mechanisms that underpin viral replication, immune evasion, and pathogenesis. 11 This examination is particularly relevant for intracellular proteins, as they play a pivotal role in the lifecycle of the virus and its interactions with host cells. 12,13 Among the intracellular proteins, RdRp is a key player in the viral life cycle, which serves as the primary enzyme responsible for replicating the viral genome.…”