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

• Published in: Journal of chemical information and modeling 2022-06, Vol.62 (11), p.2857-2868
• Main Authors: Lima Neto, José X., Vieira, Davi S., de Andrade, Jones, Fulco, Umberto Laino
• Format: Article
• Language: English
• Subjects: Binding sites; Computational Biochemistry; Coronavirus NL63, Human - metabolism; Coronaviruses; COVID-19; Density functional theory; Humans; Pandemics; Proteins; Residues; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - metabolism; Viral diseases
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.1c01544

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.