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.