TY - JOUR
T1 - Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants
AU - Das, Jayanta Kumar
AU - Thakuri, Bikash
AU - Mohankumar, Krishnan
AU - Roy, Swarup
AU - Sljoka, Adnan
AU - Sun, Gui Quan
AU - Chakraborty, Amit
N1 - Funding Information:
The authors thank all colleagues and project students of the School of Physical Sciences, Sikkim University, for their support while completing computational work in the numerical lab. The authors are also grateful to Professor Lawrence M Nogee, Johns Hopkins University School of Medicine, for his encouragement while working on this manuscript. The project was funded by the National Natural Science Foundation of China under Grant no. 12022113 and the Henry Fok foundation for young teachers (171002). a
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/11/23
Y1 - 2021/11/23
N2 - 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.
AB - 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.
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U2 - 10.1021/acsomega.1c05155
DO - 10.1021/acsomega.1c05155
M3 - Article
C2 - 34805715
AN - SCOPUS:85119409098
SN - 2470-1343
VL - 6
SP - 31305
EP - 31320
JO - ACS Omega
JF - ACS Omega
IS - 46
ER -