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In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor.
Brief Bioinform. 2021 11 05; 22(6)BB

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel coronavirus, has brought an unprecedented pandemic to the world and affected over 64 million people. The virus infects human using its spike glycoprotein mediated by a crucial area, receptor-binding domain (RBD), to bind to the human ACE2 (hACE2) receptor. Mutations on RBD have been observed in different countries and classified into nine types: A435S, D364Y, G476S, N354D/D364Y, R408I, V341I, V367F, V483A and W436R. Employing molecular dynamics (MD) simulation, we investigated dynamics and structures of the complexes of the prototype and mutant types of SARS-CoV-2 spike RBDs and hACE2. We then probed binding free energies of the prototype and mutant types of RBD with hACE2 protein by using an end-point molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. According to the result of MM-PBSA binding free energy calculations, we found that V367F and N354D/D364Y mutant types showed enhanced binding affinities with hACE2 compared to the prototype. Our computational protocols were validated by the successful prediction of relative binding free energies between prototype and three mutants: N354D/D364Y, V367F and W436R. Thus, this study provides a reliable computational protocol to fast assess the existing and emerging RBD mutations. More importantly, the binding hotspots identified by using the molecular mechanics generalized Born surface area (MM-GBSA) free energy decomposition approach can guide the rational design of small molecule drugs or vaccines free of drug resistance, to interfere with or eradicate spike-hACE2 binding.

Authors+Show Affiliations

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34013346

Citation

Zhang, Yuzhao, et al. "In Silico Binding Profile Characterization of SARS-CoV-2 Spike Protein and Its Mutants Bound to Human ACE2 Receptor." Briefings in Bioinformatics, vol. 22, no. 6, 2021.
Zhang Y, He X, Zhai J, et al. In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor. Brief Bioinform. 2021;22(6).
Zhang, Y., He, X., Zhai, J., Ji, B., Man, V. H., & Wang, J. (2021). In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor. Briefings in Bioinformatics, 22(6). https://doi.org/10.1093/bib/bbab188
Zhang Y, et al. In Silico Binding Profile Characterization of SARS-CoV-2 Spike Protein and Its Mutants Bound to Human ACE2 Receptor. Brief Bioinform. 2021 11 5;22(6) PubMed PMID: 34013346.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor. AU - Zhang,Yuzhao, AU - He,Xibing, AU - Zhai,Jingchen, AU - Ji,Beihong, AU - Man,Viet Hoang, AU - Wang,Junmei, PY - 2020/12/08/received PY - 2021/03/30/revised PY - 2021/04/22/accepted PY - 2021/5/21/pubmed PY - 2021/11/16/medline PY - 2021/5/20/entrez KW - COVID-19 KW - Free energy calculation and decomposition KW - Hotspot residues KW - MD simulation KW - Protein–protein interaction KW - SARS-CoV-2 KW - Spike RBD/hACE2 JF - Briefings in bioinformatics JO - Brief Bioinform VL - 22 IS - 6 N2 - Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel coronavirus, has brought an unprecedented pandemic to the world and affected over 64 million people. The virus infects human using its spike glycoprotein mediated by a crucial area, receptor-binding domain (RBD), to bind to the human ACE2 (hACE2) receptor. Mutations on RBD have been observed in different countries and classified into nine types: A435S, D364Y, G476S, N354D/D364Y, R408I, V341I, V367F, V483A and W436R. Employing molecular dynamics (MD) simulation, we investigated dynamics and structures of the complexes of the prototype and mutant types of SARS-CoV-2 spike RBDs and hACE2. We then probed binding free energies of the prototype and mutant types of RBD with hACE2 protein by using an end-point molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. According to the result of MM-PBSA binding free energy calculations, we found that V367F and N354D/D364Y mutant types showed enhanced binding affinities with hACE2 compared to the prototype. Our computational protocols were validated by the successful prediction of relative binding free energies between prototype and three mutants: N354D/D364Y, V367F and W436R. Thus, this study provides a reliable computational protocol to fast assess the existing and emerging RBD mutations. More importantly, the binding hotspots identified by using the molecular mechanics generalized Born surface area (MM-GBSA) free energy decomposition approach can guide the rational design of small molecule drugs or vaccines free of drug resistance, to interfere with or eradicate spike-hACE2 binding. SN - 1477-4054 UR - https://www.unboundmedicine.com/medline/citation/34013346/In_silico_binding_profile_characterization_of_SARS_CoV_2_spike_protein_and_its_mutants_bound_to_human_ACE2_receptor_ DB - PRIME DP - Unbound Medicine ER -