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

Authors

Hamid Hadi-Alijanvand, Institute for Advanced Studies in Basic Sciences, Iran
Luisa Di Paola, Università Campus Bio-Medico di Roma
Guang Hu, Soochow University
David M. Leitner, University of Nevada, Reno
Gennady M. Verkhivker, Chapman UniversityFollow
Peixin Sun, Soochow University
Humanath Poudel, University of Nevada, Reno
Alessandro Giuliani, Istituto Superiore di Sanità

Document Type

Article

Publication Date

5-10-2022

Abstract

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.

Comments

This article was originally published in ACS Omega, volume 7, issue 20, in 2022. https://doi.org/10.1021/acsomega.2c00154

This scholarship is part of the Chapman University COVID-19 Archives.

Recommended Citation

Hadi-Alijanvand H, Di Paola L, Hu G, et al. Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach. ACS Omega. 2022;7(20):17024-17042. https://doi.org/10.1021/acsomega.2c00154

Peer Reviewed

1

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.