Tags

Type your tag names separated by a space and hit enter

Effect of mutation on structure, function and dynamics of receptor binding domain of human SARS-CoV-2 with host cell receptor ACE2: a molecular dynamics simulations study.
J Biomol Struct Dyn. 2021 11; 39(18):7231-7245.JB

Abstract

Recent studies have pointed the role of angiotensin-converting enzyme-II (ACE2) in mediating the entry of SARS-CoV-2 to the host cell by binding to the receptor-binding domain (RBD) of viral spike protein, and successive priming by cellular proteases initiates the infection. SARS-CoV replication rate and disease severity is controlled by the binding affinity of RBD with ACE2. To understand, how mutations in the conserved residues of RBD affect the molecular interaction with ACE2, we generated five alanine mutants i.e. Y449A, N487A, Y489A, N501A and Y505A in the receptor binding motif (RBM) of the ACE2-RBD SARS-CoV-2 complex (PDB: 6M0J). Computational site directed mutagenesis induced dynamics in wild-type and mutant complexes were extensively studied through all-atoms molecular dynamics (MD) simulations of 150 ns. In silico mutational analysis revealed loss of important intermolecular hydrogen bonds and other non-bonded contacts, critical for molecular recognition of SARS-CoV-2 RBD to ACE2, which is well supported by saturation mutagenesis study of binding interface residues. MD simulations results showed that RBM motif is flexible, where mutant residues are relatively more mobile than corresponding wild-type residues. Global motion analysis through principal component studies revealed that RBD exhibits protuberant in-ward motion towards the human ACE2 binding interface which may be crucial for molecular interaction. Conclusively, the present finding are in congruence with previous experimental reports and provides detailed information on the structural basis of receptor binding by human SARS-CoV-2, which will crucial for the development of novel inhibitors or drugs to combat against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Authors+Show Affiliations

School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India.School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India.School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India. KIIT-Technology Business Incubator (KIIT-TBI), Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India.School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India. KIIT-Technology Business Incubator (KIIT-TBI), Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32762417

Citation

Dehury, Budheswar, et al. "Effect of Mutation On Structure, Function and Dynamics of Receptor Binding Domain of Human SARS-CoV-2 With Host Cell Receptor ACE2: a Molecular Dynamics Simulations Study." Journal of Biomolecular Structure & Dynamics, vol. 39, no. 18, 2021, pp. 7231-7245.
Dehury B, Raina V, Misra N, et al. Effect of mutation on structure, function and dynamics of receptor binding domain of human SARS-CoV-2 with host cell receptor ACE2: a molecular dynamics simulations study. J Biomol Struct Dyn. 2021;39(18):7231-7245.
Dehury, B., Raina, V., Misra, N., & Suar, M. (2021). Effect of mutation on structure, function and dynamics of receptor binding domain of human SARS-CoV-2 with host cell receptor ACE2: a molecular dynamics simulations study. Journal of Biomolecular Structure & Dynamics, 39(18), 7231-7245. https://doi.org/10.1080/07391102.2020.1802348
Dehury B, et al. Effect of Mutation On Structure, Function and Dynamics of Receptor Binding Domain of Human SARS-CoV-2 With Host Cell Receptor ACE2: a Molecular Dynamics Simulations Study. J Biomol Struct Dyn. 2021;39(18):7231-7245. PubMed PMID: 32762417.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of mutation on structure, function and dynamics of receptor binding domain of human SARS-CoV-2 with host cell receptor ACE2: a molecular dynamics simulations study. AU - Dehury,Budheswar, AU - Raina,Vishakha, AU - Misra,Namrata, AU - Suar,Mrutyunjay, Y1 - 2020/08/07/ PY - 2020/8/9/pubmed PY - 2021/10/21/medline PY - 2020/8/9/entrez KW - MD simulation KW - SARS-CoV-2 KW - angiotensin-converting enzyme-II KW - coronavirus KW - receptor binding motif SP - 7231 EP - 7245 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 39 IS - 18 N2 - Recent studies have pointed the role of angiotensin-converting enzyme-II (ACE2) in mediating the entry of SARS-CoV-2 to the host cell by binding to the receptor-binding domain (RBD) of viral spike protein, and successive priming by cellular proteases initiates the infection. SARS-CoV replication rate and disease severity is controlled by the binding affinity of RBD with ACE2. To understand, how mutations in the conserved residues of RBD affect the molecular interaction with ACE2, we generated five alanine mutants i.e. Y449A, N487A, Y489A, N501A and Y505A in the receptor binding motif (RBM) of the ACE2-RBD SARS-CoV-2 complex (PDB: 6M0J). Computational site directed mutagenesis induced dynamics in wild-type and mutant complexes were extensively studied through all-atoms molecular dynamics (MD) simulations of 150 ns. In silico mutational analysis revealed loss of important intermolecular hydrogen bonds and other non-bonded contacts, critical for molecular recognition of SARS-CoV-2 RBD to ACE2, which is well supported by saturation mutagenesis study of binding interface residues. MD simulations results showed that RBM motif is flexible, where mutant residues are relatively more mobile than corresponding wild-type residues. Global motion analysis through principal component studies revealed that RBD exhibits protuberant in-ward motion towards the human ACE2 binding interface which may be crucial for molecular interaction. Conclusively, the present finding are in congruence with previous experimental reports and provides detailed information on the structural basis of receptor binding by human SARS-CoV-2, which will crucial for the development of novel inhibitors or drugs to combat against SARS-CoV-2.Communicated by Ramaswamy H. Sarma. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/32762417/Effect_of_mutation_on_structure_function_and_dynamics_of_receptor_binding_domain_of_human_SARS_CoV_2_with_host_cell_receptor_ACE2:_a_molecular_dynamics_simulations_study_ L2 - https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1802348 DB - PRIME DP - Unbound Medicine ER -