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Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation

The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting e...

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Autores principales: Du, Yaoqiang, Wang, Hao, Chen, Linjie, Fang, Quan, Zhang, Biqin, Jiang, Luxi, Wu, Zhaoyu, Yang, Yexiaoqing, Zhou, Ying, Chen, Bingyu, Lyu, Jianxin, Wang, Zhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353372/
https://www.ncbi.nlm.nih.gov/pubmed/34386518
http://dx.doi.org/10.3389/fmolb.2021.614443
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author Du, Yaoqiang
Wang, Hao
Chen, Linjie
Fang, Quan
Zhang, Biqin
Jiang, Luxi
Wu, Zhaoyu
Yang, Yexiaoqing
Zhou, Ying
Chen, Bingyu
Lyu, Jianxin
Wang, Zhen
author_facet Du, Yaoqiang
Wang, Hao
Chen, Linjie
Fang, Quan
Zhang, Biqin
Jiang, Luxi
Wu, Zhaoyu
Yang, Yexiaoqing
Zhou, Ying
Chen, Bingyu
Lyu, Jianxin
Wang, Zhen
author_sort Du, Yaoqiang
collection PubMed
description The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor was shown to initiate coronavirus entry into host cells and lead to their infection. The receptor-binding motif (RBM, 438–506) is a region that directly interacts with ACE2 receptor in the RBD and plays a crucial role in determining affinity. To unravel how mutations in the non-RBM regions impact the interaction between RBD and ACE2, we selected three non-RBM mutant systems (N354D, D364Y, and V367F) from the documented clinical cases, and the Q498A mutant system located in the RBM region served as the control. Molecular dynamics simulation was conducted on the mutant systems and the wild-type (WT) system, and verified experiments also performed. Non-RBM mutations have been shown not only to change conformation of the RBM region but also to significantly influence its hydrogen bonding and hydrophobic interactions. In particular, the D364Y and V367F systems showed a higher affinity for ACE2 owing to their electrostatic interactions and polar solvation energy changes. In addition, although the binding free energy at this point increased after the mutation of N354D, the conformation of the random coil (Pro384-Asp389) was looser than that of other systems, and the combined effect weakened the binding free energy between RBD and ACE2. Interestingly, we also found a random coil (Ala475-Gly485). This random coil is very sensitive to mutations, and both types of mutations increase the binding free energy of residues in this region. We found that the binding loop (Tyr495-Tyr505) in the RBD domain strongly binds to Lys353, an important residue of the ACE2 domain previously identified. The binding free energy of the non-RBM mutant group at the binding loop had positive and negative changes, and these changes were more obvious than that of the Q498A system. The results of this study elucidate the effect of non-RBM mutation on ACE2-RBD binding, and provide new insights for SARS-CoV-2 mutation research.
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spelling pubmed-83533722021-08-11 Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation Du, Yaoqiang Wang, Hao Chen, Linjie Fang, Quan Zhang, Biqin Jiang, Luxi Wu, Zhaoyu Yang, Yexiaoqing Zhou, Ying Chen, Bingyu Lyu, Jianxin Wang, Zhen Front Mol Biosci Molecular Biosciences The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor was shown to initiate coronavirus entry into host cells and lead to their infection. The receptor-binding motif (RBM, 438–506) is a region that directly interacts with ACE2 receptor in the RBD and plays a crucial role in determining affinity. To unravel how mutations in the non-RBM regions impact the interaction between RBD and ACE2, we selected three non-RBM mutant systems (N354D, D364Y, and V367F) from the documented clinical cases, and the Q498A mutant system located in the RBM region served as the control. Molecular dynamics simulation was conducted on the mutant systems and the wild-type (WT) system, and verified experiments also performed. Non-RBM mutations have been shown not only to change conformation of the RBM region but also to significantly influence its hydrogen bonding and hydrophobic interactions. In particular, the D364Y and V367F systems showed a higher affinity for ACE2 owing to their electrostatic interactions and polar solvation energy changes. In addition, although the binding free energy at this point increased after the mutation of N354D, the conformation of the random coil (Pro384-Asp389) was looser than that of other systems, and the combined effect weakened the binding free energy between RBD and ACE2. Interestingly, we also found a random coil (Ala475-Gly485). This random coil is very sensitive to mutations, and both types of mutations increase the binding free energy of residues in this region. We found that the binding loop (Tyr495-Tyr505) in the RBD domain strongly binds to Lys353, an important residue of the ACE2 domain previously identified. The binding free energy of the non-RBM mutant group at the binding loop had positive and negative changes, and these changes were more obvious than that of the Q498A system. The results of this study elucidate the effect of non-RBM mutation on ACE2-RBD binding, and provide new insights for SARS-CoV-2 mutation research. Frontiers Media S.A. 2021-07-27 /pmc/articles/PMC8353372/ /pubmed/34386518 http://dx.doi.org/10.3389/fmolb.2021.614443 Text en Copyright © 2021 Du, Wang, Chen, Fang, Zhang, Jiang, Wu, Yang, Zhou, Chen, Lyu and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Du, Yaoqiang
Wang, Hao
Chen, Linjie
Fang, Quan
Zhang, Biqin
Jiang, Luxi
Wu, Zhaoyu
Yang, Yexiaoqing
Zhou, Ying
Chen, Bingyu
Lyu, Jianxin
Wang, Zhen
Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation
title Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation
title_full Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation
title_fullStr Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation
title_full_unstemmed Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation
title_short Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation
title_sort non-rbm mutations impaired sars-cov-2 spike protein regulated to the ace2 receptor based on molecular dynamic simulation
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353372/
https://www.ncbi.nlm.nih.gov/pubmed/34386518
http://dx.doi.org/10.3389/fmolb.2021.614443
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