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Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence.
ACS Nano. 2021 04 27; 15(4):6929-6948.AN

Abstract

The coronavirus disease-2019 (COVID-19) pandemic, caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in China during late 2019 and swiftly spread worldwide. Since COVID-19 emergence, many therapeutic regimens have been relentlessly explored, and although two vaccines have just received emergency use authorization by different governmental agencies, antiviral therapeutics based neutralizing antibodies and small-drug inhibitors can still be vital viable options to prevent and treat SARS-CoV-2 infections. The viral spike glycoprotein (S-protein) is the key molecular player that promotes human host cellular invasion via recognition of and binding to the angiotensin-converting enzyme 2 gene (ACE2). In this work, we report the results obtained by mutating in silico the 18 ACE2 residues and the 14 S-protein receptor binding domain (S-RBDCoV-2) residues that contribute to the receptor/viral protein binding interface. Specifically, each wild-type protein-protein interface residue was replaced by a hydrophobic (isoleucine), polar (serine and threonine), charged (aspartic acid/glutamic acid and lysine/arginine), and bulky (tryptophan) residue, respectively, in order to study the different effects exerted by nature, shape, and dimensions of the mutant amino acids on the structure and strength of the resulting binding interface. The computational results were next validated a posteriori against the corresponding experimental data, yielding an overall agreement of 92%. Interestingly, a non-negligible number of mis-sense variations were predicted to enhance ACE2/S-RBDCoV-2 binding, including the variants Q24T, T27D/K/W, D30E, H34S7T/K, E35D, Q42K, L79I/W, R357K, and R393K on ACE2 and L455D/W, F456K/W, Q493K, N501T, and Y505W on S-RBDCoV-2, respectively.

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

33733740

Citation

Laurini, Erik, et al. "Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison With Experimental Evidence." ACS Nano, vol. 15, no. 4, 2021, pp. 6929-6948.
Laurini E, Marson D, Aulic S, et al. Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence. ACS Nano. 2021;15(4):6929-6948.
Laurini, E., Marson, D., Aulic, S., Fermeglia, A., & Pricl, S. (2021). Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence. ACS Nano, 15(4), 6929-6948. https://doi.org/10.1021/acsnano.0c10833
Laurini E, et al. Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison With Experimental Evidence. ACS Nano. 2021 04 27;15(4):6929-6948. PubMed PMID: 33733740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence. AU - Laurini,Erik, AU - Marson,Domenico, AU - Aulic,Suzana, AU - Fermeglia,Alice, AU - Pricl,Sabrina, Y1 - 2021/03/18/ PY - 2021/3/19/pubmed PY - 2021/5/15/medline PY - 2021/3/18/entrez KW - ACE2 KW - SARS-CoV-2 spike protein KW - computational mutagenesis KW - free energy of binding KW - molecular dynamics KW - molecular mechanics/Poisson−Boltzmann surface area (MM/PBSA) KW - receptor binding domain SP - 6929 EP - 6948 JF - ACS nano JO - ACS Nano VL - 15 IS - 4 N2 - The coronavirus disease-2019 (COVID-19) pandemic, caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in China during late 2019 and swiftly spread worldwide. Since COVID-19 emergence, many therapeutic regimens have been relentlessly explored, and although two vaccines have just received emergency use authorization by different governmental agencies, antiviral therapeutics based neutralizing antibodies and small-drug inhibitors can still be vital viable options to prevent and treat SARS-CoV-2 infections. The viral spike glycoprotein (S-protein) is the key molecular player that promotes human host cellular invasion via recognition of and binding to the angiotensin-converting enzyme 2 gene (ACE2). In this work, we report the results obtained by mutating in silico the 18 ACE2 residues and the 14 S-protein receptor binding domain (S-RBDCoV-2) residues that contribute to the receptor/viral protein binding interface. Specifically, each wild-type protein-protein interface residue was replaced by a hydrophobic (isoleucine), polar (serine and threonine), charged (aspartic acid/glutamic acid and lysine/arginine), and bulky (tryptophan) residue, respectively, in order to study the different effects exerted by nature, shape, and dimensions of the mutant amino acids on the structure and strength of the resulting binding interface. The computational results were next validated a posteriori against the corresponding experimental data, yielding an overall agreement of 92%. Interestingly, a non-negligible number of mis-sense variations were predicted to enhance ACE2/S-RBDCoV-2 binding, including the variants Q24T, T27D/K/W, D30E, H34S7T/K, E35D, Q42K, L79I/W, R357K, and R393K on ACE2 and L455D/W, F456K/W, Q493K, N501T, and Y505W on S-RBDCoV-2, respectively. SN - 1936-086X UR - https://www.unboundmedicine.com/medline/citation/33733740/Computational_Mutagenesis_at_the_SARS_CoV_2_Spike_Protein/Angiotensin_Converting_Enzyme_2_Binding_Interface:_Comparison_with_Experimental_Evidence_ L2 - https://doi.org/10.1021/acsnano.0c10833 DB - PRIME DP - Unbound Medicine ER -