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

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.

Electrostatic Features for the Receptor Binding Domain of SARS-COV-2 Wildtype and Its Variants. Compass to the Severity of the Future Variants with the Charge-Rule

“…From the theoretical perspective (in chronological order), the RBD-ACE2 and RBD-binders’ biological interfaces for the SARS-CoV-2 wt were investigated at the beginning of the COVID19 pandemic by Giron and colleagues and followed by several other works (e.g., refs , , , , and − ). In the study carried out by Giron and coauthors, it was demonstrated using a constant-pH coarse-grained model and Monte Carlo (MC) simulations that the RBD of SARS-CoV-2 wt could bind to ACE2 with similar binding affinities to SARS-CoV-1.…”

Electrostatic features for the Receptor binding domain of SARS-COV-2 wildtype and its variants. Compass to the severity of the future variants with the charge-rule

“…refs. 24,[41][42][43][44][45][46][47][48][49] ). In the study carried out by Giron and co-authors, it was demonstrated using a constant-pH coarse-grained model and Monte Carlo (MC) simulations that the RBD of SARS-CoV-2 wt could bind to ACE2 with similar binding affinities to SARS-CoV-1.…”

Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases

“…In the last few years, the COVID-19 pandemic prompted a multitude of investigations on the pathogeny of this new virus and also on the patent neurological disturbances shown in a series of cases, the infamous ”long COVID” [ 208 ] and its co-involvement with the RAS system [ 209 ]. A series of experimental results demonstrated that SARS-CoV-2 penetration is made at the level of the ACE receptor, mediated through the spike protein [ 210 ] connecting with the ACE2 receptor in the presence of calcium [ 211 ]. The deleterious effects on the CNS are similar to viral encephalitis or systemic inflammation, but some suspect an involvement of protein misfolding with an evolution towards NDG disease, with cognitive deficiencies or motor deficits [ 212 , 213 ].…”