Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

被引:30
作者
Alaofi, Ahmed L. [1 ]
Shahid, Mudassar [1 ]
机构
[1] King Saud Univ, Coll Pharm, Dept Pharmaceut, POB 2457, Riyadh 11451, Saudi Arabia
关键词
wild-type RBD; mutant RBDs; SARS-CoV-2; molecular dynamics simulations; RBD flexibility; principle component analysis; free energy landscape; RECEPTOR-BINDING; PROTEIN-PROTEIN; DYNAMICS; RECOGNITION; FLEXIBILITY; MECHANISMS; DOMAIN; ENTRY;
D O I
10.3390/biom11091273
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates the viral-host interaction and is a target for most neutralizing antibodies. Nevertheless, SARS-CoV-2 RBD mutations pose a threat due to their role in host cell entry via the human angiotensin-converting enzyme 2 receptor that might strengthen SARS-CoV-2 infectivity, viral load, or resistance against neutralizing antibodies. To understand the molecular structural link between RBD mutations and infectivity, the top five mutant RBDs (i.e., N501Y, E484K L452R, S477N, and N439K) were selected based on their recorded case numbers. These mutants along with wild-type (WT) RBD were studied through all-atom molecular dynamics (MD) simulations of 100 ns. The principal component analysis and the free energy landscape were used too. Interestingly, N501Y, N439K, and E484K mutations were observed to increase the rigidity in some RBD regions while increasing the flexibility of the receptor-binding motif (RBM) region, suggesting a compensation of the entropy penalty. However, S477N and L452R RBDs were observed to increase the flexibility of the RBM region while maintaining similar flexibility in other RBD regions in comparison to WT RBD. Therefore, both mutations (especially S477N) might destabilize the RBD structure, as loose conformation compactness was observed. The destabilizing effect of S477N RBD was consistent with previous work on S477N mutation. Finally, the free energy landscape results showed that mutations changed WT RBD conformation while local minima were maintained for all mutant RBDs. In conclusion, RBD mutations definitely impact the WT RBD structure and conformation as well as increase the binding affinity to angiotensin-converting enzyme receptor.
引用
收藏
页数:15
相关论文
共 60 条
[1]   Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers [J].
Abraham, Mark James ;
Murtola, Teemu ;
Schulz, Roland ;
Páll, Szilárd ;
Smith, Jeremy C. ;
Hess, Berk ;
Lindah, Erik .
SoftwareX, 2015, 1-2 :19-25
[2]   CovMT: an interactive SARS-CoV-2 mutation tracker, with a focus on critical variants [J].
Alam, Intikhab ;
Radovanovic, Aleksandar ;
Incitti, Roberto ;
Kamau, Allan A. ;
Alarawi, Mohammed ;
Azhar, Esam I. ;
Gojobori, Takashi .
LANCET INFECTIOUS DISEASES, 2021, 21 (05) :602-602
[3]   Probing the interaction between cHAVc3 peptide and the EC1 domain of E-cadherin using NMR and molecular dynamics simulations [J].
Alaofi, Ahmed ;
Farokhi, Elinaz ;
Prasasty, Vivitri D. ;
Anbanandam, Asokan ;
Kuczera, Krzysztof ;
Siahaan, Teruna J. .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2017, 35 (01) :92-104
[4]   Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors [J].
Alaofi, Ahmed L. .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2022, 40 (02) :752-763
[5]   Probing the flexibility of Zika virus envelope protein DIII epitopes using molecular dynamics simulations [J].
Alaofi, Ahmed L. .
MOLECULAR SIMULATION, 2020, 46 (07) :541-547
[6]   Main-chain conformational tendencies of amino acids [J].
Anderson, RJ ;
Weng, ZP ;
Campbell, RK ;
Jiang, XL .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2005, 60 (04) :679-689
[7]   SARS-CoV-2 viral spike G614 mutation exhibits higher case fatality rate [J].
Becerra-Flores, Manuel ;
Cardozo, Timothy .
INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, 2020, 74 (08)
[8]   Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients' B Cells [J].
Cao, Yunlong ;
Su, Bin ;
Guo, Xianghua ;
Sun, Wenjie ;
Deng, Yongqiang ;
Bao, Linlin ;
Zhu, Qinyu ;
Zhang, Xu ;
Zheng, Yinghui ;
Geng, Chenyang ;
Chai, Xiaoran ;
He, Runsheng ;
Li, Xiaofeng ;
Lv, Qi ;
Zhu, Hua ;
Deng, Wei ;
Xu, Yanfeng ;
Wang, Yanjun ;
Qiao, Luxin ;
Tan, Yafang ;
Song, Liyang ;
Wang, Guopeng ;
Du, Xiaoxia ;
Gao, Ning ;
Liu, Jiangning ;
Xiao, Junyu ;
Su, Xiao-dong ;
Du, Zongmin ;
Feng, Yingmei ;
Qin, Chuan ;
Qin, Chengfeng ;
Jin, Ronghua ;
Xie, X. Sunney .
CELL, 2020, 182 (01) :73-+
[9]   Mutations Strengthened SARS-CoV-2 Infectivity [J].
Chen, Jiahui ;
Wang, Rui ;
Wang, Menglun ;
Wei, Guo-Wei .
JOURNAL OF MOLECULAR BIOLOGY, 2020, 432 (19) :5212-5226
[10]   Molecular cloning, GTP recognition mechanism and tissue-specific expression profiling of myxovirus resistance (Mx) protein in Labeo rohita (Hamilton) after Poly I: C induction [J].
Das, Basanta Kumar ;
Roy, Pragyan ;
Rout, Ajaya Kumar ;
Sahoo, Deepak Ranjan ;
Panda, Soumya Prasad ;
Pattanaik, Sushmita ;
Dehury, Budheswar ;
Behera, Bijay Kumar ;
Mishra, Sudhansu Sekhar .
SCIENTIFIC REPORTS, 2019, 9 (1)