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Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex.
ACS Nano. 2020 09 22; 14(9):11821-11830.AN

Abstract

The recent emergence of the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent for the coronavirus disease 2019 (COVID-19), is causing a global pandemic that poses enormous challenges to global public health and economies. SARS-CoV-2 host cell entry is mediated by the interaction of the viral transmembrane spike glycoprotein (S-protein) with the angiotensin-converting enzyme 2 gene (ACE2), an essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Accordingly, this work reports an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the SARS-CoV-2 S-protein and its host cellular receptor ACE2 that provides qualitative and quantitative insights into the main molecular determinants in virus/receptor recognition. In particular, residues D38, K31, E37, K353, and Y41 on ACE2 and Q498, T500, and R403 on the SARS-CoV-2 S-protein receptor-binding domain are determined as true hot spots, contributing to shaping and determining the stability of the relevant protein-protein interface. Overall, these results could be used to estimate the binding affinity of the viral protein to different allelic variants of ACE2 receptors discovered in COVID-19 patients and for the effective structure-based design and development of neutralizing antibodies, vaccines, and protein/protein inhibitors against this terrible new coronavirus.

Authors+Show Affiliations

Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy.Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy.Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy.Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy.Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy. Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32833435

Citation

Laurini, Erik, et al. "Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex." ACS Nano, vol. 14, no. 9, 2020, pp. 11821-11830.
Laurini E, Marson D, Aulic S, et al. Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex. ACS Nano. 2020;14(9):11821-11830.
Laurini, E., Marson, D., Aulic, S., Fermeglia, M., & Pricl, S. (2020). Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex. ACS Nano, 14(9), 11821-11830. https://doi.org/10.1021/acsnano.0c04674
Laurini E, et al. Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex. ACS Nano. 2020 09 22;14(9):11821-11830. PubMed PMID: 32833435.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex. AU - Laurini,Erik, AU - Marson,Domenico, AU - Aulic,Suzana, AU - Fermeglia,Maurizio, AU - Pricl,Sabrina, Y1 - 2020/08/26/ PY - 2020/8/25/pubmed PY - 2020/10/24/medline PY - 2020/8/25/entrez KW - ACE2 KW - SARS-CoV-2 spike protein KW - computational alanine-scanning mutagenesis KW - free energy of binding KW - molecular dynamics KW - molecular mechanics/Poisson−Boltzmann surface area KW - receptor-binding domain SP - 11821 EP - 11830 JF - ACS nano JO - ACS Nano VL - 14 IS - 9 N2 - The recent emergence of the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent for the coronavirus disease 2019 (COVID-19), is causing a global pandemic that poses enormous challenges to global public health and economies. SARS-CoV-2 host cell entry is mediated by the interaction of the viral transmembrane spike glycoprotein (S-protein) with the angiotensin-converting enzyme 2 gene (ACE2), an essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Accordingly, this work reports an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the SARS-CoV-2 S-protein and its host cellular receptor ACE2 that provides qualitative and quantitative insights into the main molecular determinants in virus/receptor recognition. In particular, residues D38, K31, E37, K353, and Y41 on ACE2 and Q498, T500, and R403 on the SARS-CoV-2 S-protein receptor-binding domain are determined as true hot spots, contributing to shaping and determining the stability of the relevant protein-protein interface. Overall, these results could be used to estimate the binding affinity of the viral protein to different allelic variants of ACE2 receptors discovered in COVID-19 patients and for the effective structure-based design and development of neutralizing antibodies, vaccines, and protein/protein inhibitors against this terrible new coronavirus. SN - 1936-086X UR - https://www.unboundmedicine.com/medline/citation/32833435/Computational_Alanine_Scanning_and_Structural_Analysis_of_the_SARS_CoV_2_Spike_Protein/Angiotensin_Converting_Enzyme_2_Complex_ L2 - https://doi.org/10.1021/acsnano.0c04674 DB - PRIME DP - Unbound Medicine ER -