Exploring the Spike-hACE 2 Residue–Residue Interaction in Human Coronaviruses SARS-CoV-2, SARS-CoV, and HCoV-NL63

Coronaviruses
(CoVs) have been responsible for three major outbreaks
since the beginning of the 21st century, and the emergence of the
recent COVID-19 pandemic has resulted in considerable efforts to design
new therapies against coronaviruses. Thus, it is crucial to understand
the structural features of their major proteins related to the virus–host
interaction. Several studies have shown that from the seven known
CoV human pathogens, three of them use the human Angiotensin-Converting
Enzyme 2 (hACE-2) to mediate their host’s cell entry: SARS-CoV-2,
SARS-CoV, and HCoV-NL63. Therefore, we employed quantum biochemistry
techniques within the density function theory (DFT) framework and
the molecular fragmentation with conjugate caps (MFCC) approach to
analyze the interactions between the hACE-2 and the spike protein-RBD
of the three CoVs in order to map the hot-spot residues that form
the recognition surface for these complexes and define the similarities
and differences in the interaction scenario. The total interaction
energy evaluated showed a good agreement with the experimental binding
affinity order: SARS-2 > SARS > NL63. A detailed investigation
revealed
the energetically most relevant regions of hACE-2 and the spike protein
for each complex, as well as the key residue–residue interactions.
Our results provide valuable information to deeply understand the
structural behavior and binding site characteristics that could help
to develop antiviral therapeutics that inhibit protein–protein
interactions between CoVs S protein and hACE-2.