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The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach.
J Proteome Res. 2020 Nov 06; 19(11):4576-4586.JP

Abstract

SARS-CoV-2 has caused the largest pandemic of the twenty-first century (COVID-19), threatening the life and economy of all countries in the world. The identification of novel therapies and vaccines that can mitigate or control this global health threat is among the most important challenges facing biomedical sciences. To construct a long-term strategy to fight both SARS-CoV-2 and other possible future threats from coronaviruses, it is critical to understand the molecular mechanisms underlying the virus action. The viral entry and associated infectivity stems from the formation of the SARS-CoV-2 spike protein complex with angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein molecule can be used to elucidate the molecular pathways that can be targeted with allosteric drugs to weaken the spike-ACE2 interaction and, thus, reduce viral infectivity. In this study, we present the results of the application of different computational methods aimed at detecting allosteric sites on the SARS-CoV-2 spike protein. The adopted tools consisted of the protein contact networks (PCNs), SEPAS (Affinity by Flexibility), and perturbation response scanning (PRS) based on elastic network modes. All of these methods were applied to the ACE2 complex with both the SARS-CoV2 and SARS-CoV spike proteins. All of the adopted analyses converged toward a specific region (allosteric modulation region [AMR]), present in both complexes and predicted to act as an allosteric site modulating the binding of the spike protein with ACE2. Preliminary results on hepcidin (a molecule with strong structural and sequence with AMR) indicated an inhibitory effect on the binding affinity of the spike protein toward the ACE2 protein.

Authors+Show Affiliations

Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Engineering, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy.Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, 45137-66731, Iran.Center for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.Center for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.Environmental and Health Department, Istituto Superiore di Sanità, 00161 Rome, Italy.

Pub Type(s)

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

Language

eng

PubMed ID

32551648

Citation

Di Paola, Luisa, et al. "The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach." Journal of Proteome Research, vol. 19, no. 11, 2020, pp. 4576-4586.
Di Paola L, Hadi-Alijanvand H, Song X, et al. The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach. J Proteome Res. 2020;19(11):4576-4586.
Di Paola, L., Hadi-Alijanvand, H., Song, X., Hu, G., & Giuliani, A. (2020). The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach. Journal of Proteome Research, 19(11), 4576-4586. https://doi.org/10.1021/acs.jproteome.0c00273
Di Paola L, et al. The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach. J Proteome Res. 2020 Nov 6;19(11):4576-4586. PubMed PMID: 32551648.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach. AU - Di Paola,Luisa, AU - Hadi-Alijanvand,Hamid, AU - Song,Xingyu, AU - Hu,Guang, AU - Giuliani,Alessandro, Y1 - 2020/07/01/ PY - 2020/6/20/pubmed PY - 2020/12/1/medline PY - 2020/6/20/entrez KW - ACE2 binding KW - COVID-19 KW - allosteric drugs KW - binding patch softness KW - drug discovery KW - elastic networks modeling KW - protein contact networks KW - spike protein SP - 4576 EP - 4586 JF - Journal of proteome research JO - J Proteome Res VL - 19 IS - 11 N2 - SARS-CoV-2 has caused the largest pandemic of the twenty-first century (COVID-19), threatening the life and economy of all countries in the world. The identification of novel therapies and vaccines that can mitigate or control this global health threat is among the most important challenges facing biomedical sciences. To construct a long-term strategy to fight both SARS-CoV-2 and other possible future threats from coronaviruses, it is critical to understand the molecular mechanisms underlying the virus action. The viral entry and associated infectivity stems from the formation of the SARS-CoV-2 spike protein complex with angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein molecule can be used to elucidate the molecular pathways that can be targeted with allosteric drugs to weaken the spike-ACE2 interaction and, thus, reduce viral infectivity. In this study, we present the results of the application of different computational methods aimed at detecting allosteric sites on the SARS-CoV-2 spike protein. The adopted tools consisted of the protein contact networks (PCNs), SEPAS (Affinity by Flexibility), and perturbation response scanning (PRS) based on elastic network modes. All of these methods were applied to the ACE2 complex with both the SARS-CoV2 and SARS-CoV spike proteins. All of the adopted analyses converged toward a specific region (allosteric modulation region [AMR]), present in both complexes and predicted to act as an allosteric site modulating the binding of the spike protein with ACE2. Preliminary results on hepcidin (a molecule with strong structural and sequence with AMR) indicated an inhibitory effect on the binding affinity of the spike protein toward the ACE2 protein. SN - 1535-3907 UR - https://www.unboundmedicine.com/medline/citation/32551648/The_Discovery_of_a_Putative_Allosteric_Site_in_the_SARS_CoV_2_Spike_Protein_Using_an_Integrated_Structural/Dynamic_Approach_ DB - PRIME DP - Unbound Medicine ER -