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Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach

[Image: see text] At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its d...

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Autores principales: Hadi-Alijanvand, Hamid, Di Paola, Luisa, Hu, Guang, Leitner, David M., Verkhivker, Gennady M., Sun, Peixin, Poudel, Humanath, Giuliani, Alessandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113007/
https://www.ncbi.nlm.nih.gov/pubmed/35600142
http://dx.doi.org/10.1021/acsomega.2c00154
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author Hadi-Alijanvand, Hamid
Di Paola, Luisa
Hu, Guang
Leitner, David M.
Verkhivker, Gennady M.
Sun, Peixin
Poudel, Humanath
Giuliani, Alessandro
author_facet Hadi-Alijanvand, Hamid
Di Paola, Luisa
Hu, Guang
Leitner, David M.
Verkhivker, Gennady M.
Sun, Peixin
Poudel, Humanath
Giuliani, Alessandro
author_sort Hadi-Alijanvand, Hamid
collection PubMed
description [Image: see text] At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection stage, is missing. In this work, we present a multifaceted computational approach strongly grounded on a biophysical modeling of biological systems, so to disclose the interaction of the SARS-CoV2 spike protein with ACE2 with a special focus to an allosteric regulation of the spike–ACE2 interaction. Our approach includes the following methodologies: Protein Contact Networks and Network Clustering, Targeted Molecular Dynamics, Elastic Network Modeling, Perturbation Response Scanning, and a computational analysis of energy flow and SEPAS as a protein-softness and monomer-based affinity predictor. We applied this approach to free (closed and open) states of spike protein and spike–ACE2 complexes. Eventually, we analyzed the interactions of free and bound forms of spike with hepcidin (HPC), the major hormone in iron regulation, recently addressed as a central player in the COVID19 pathogenesis, with a special emphasis to the most severe outcomes. Our results demonstrate that, compared with closed and open states, the spike protein in the ACE2-bound state shows higher allosteric potential. The correspondence between hinge sites and the Allosteric Modulation Region (AMR) in the S-ACE complex suggests a molecular basis for hepcidin involvement in COVID19 pathogenesis. We verify the importance of AMR in different states of spike and then study its interactions with HPC and the consequence of the HPC-AMR interaction on spike dynamics and its affinity for ACE2. We propose two complementary mechanisms for HPC effects on spike of SARS-CoV-2; (a) HPC acts as a competitive inhibitor when spike is in a preinfection state (open and with no ACE2), (b) the HPC-AMR interaction pushes the spike structure into the safer closed state. These findings need clear molecular in vivo verification beside clinical observations.
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spelling pubmed-91130072022-05-18 Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach Hadi-Alijanvand, Hamid Di Paola, Luisa Hu, Guang Leitner, David M. Verkhivker, Gennady M. Sun, Peixin Poudel, Humanath Giuliani, Alessandro ACS Omega [Image: see text] At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection stage, is missing. In this work, we present a multifaceted computational approach strongly grounded on a biophysical modeling of biological systems, so to disclose the interaction of the SARS-CoV2 spike protein with ACE2 with a special focus to an allosteric regulation of the spike–ACE2 interaction. Our approach includes the following methodologies: Protein Contact Networks and Network Clustering, Targeted Molecular Dynamics, Elastic Network Modeling, Perturbation Response Scanning, and a computational analysis of energy flow and SEPAS as a protein-softness and monomer-based affinity predictor. We applied this approach to free (closed and open) states of spike protein and spike–ACE2 complexes. Eventually, we analyzed the interactions of free and bound forms of spike with hepcidin (HPC), the major hormone in iron regulation, recently addressed as a central player in the COVID19 pathogenesis, with a special emphasis to the most severe outcomes. Our results demonstrate that, compared with closed and open states, the spike protein in the ACE2-bound state shows higher allosteric potential. The correspondence between hinge sites and the Allosteric Modulation Region (AMR) in the S-ACE complex suggests a molecular basis for hepcidin involvement in COVID19 pathogenesis. We verify the importance of AMR in different states of spike and then study its interactions with HPC and the consequence of the HPC-AMR interaction on spike dynamics and its affinity for ACE2. We propose two complementary mechanisms for HPC effects on spike of SARS-CoV-2; (a) HPC acts as a competitive inhibitor when spike is in a preinfection state (open and with no ACE2), (b) the HPC-AMR interaction pushes the spike structure into the safer closed state. These findings need clear molecular in vivo verification beside clinical observations. American Chemical Society 2022-05-10 /pmc/articles/PMC9113007/ /pubmed/35600142 http://dx.doi.org/10.1021/acsomega.2c00154 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Hadi-Alijanvand, Hamid
Di Paola, Luisa
Hu, Guang
Leitner, David M.
Verkhivker, Gennady M.
Sun, Peixin
Poudel, Humanath
Giuliani, Alessandro
Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach
title Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach
title_full Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach
title_fullStr Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach
title_full_unstemmed Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach
title_short Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach
title_sort biophysical insight into the sars-cov2 spike–ace2 interaction and its modulation by hepcidin through a multifaceted computational approach
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113007/
https://www.ncbi.nlm.nih.gov/pubmed/35600142
http://dx.doi.org/10.1021/acsomega.2c00154
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