In silico investigation of critical binding pattern in SARS-CoV-2 spike protein with angiotensin-converting enzyme 2

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a newly-discovered coronavirus and responsible for the spread of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infected millions of people in the world and immediately became a pandemic in March 2020. SARS-CoV-2 belongs to the beta-coronavirus genus of the large family of Coronaviridae. It is now known that its surface spike glycoprotein binds to the angiotensin-converting enzyme-2 (ACE2), which is expressed on the lung epithelial cells, mediates the fusion of the cellular and viral membranes, and facilitates the entry of viral genome to the host cell. Therefore, blocking the virus-cell interaction could be a potential target for the prevention of viral infection. The binding of SARS-CoV-2 to ACE2 is a protein–protein interaction, and so, analyzing the structure of the spike glycoprotein of SARS-CoV-2 and its underlying mechanism to bind the host cell receptor would be useful for the management and treatment of COVID-19. In this study, we performed comparative in silico studies to deeply understand the structural and functional details of the interaction between the spike glycoprotein of SARS-CoV-2 and its cognate cellular receptor ACE2. According to our results, the affinity of the ACE2 receptor for SARS-CoV-2 was higher than SARS-CoV. According to the free energy decomposition of the spike glycoprotein-ACE2 complex, we found critical points in three areas which are responsible for the increased binding affinity of SARS-CoV-2 compared with SARS-CoV. These mutations occurred at the receptor-binding domain of the spike glycoprotein that play an essential role in the increasing the affinity of coronavirus to ACE2. For instance, mutations Pro462Ala and Leu472Phe resulted in the altered binding energy from − 2 kcal mol−1 in SARS-COV to − 6 kcal mol−1 in SARS-COV-2. The results demonstrated that some mutations in the receptor-binding motif could be considered as a hot-point for designing potential drugs to inhibit the interaction between the spike glycoprotein and ACE2.

The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core

“…1a). Specifically, we used the Network Analysis of Protein Structures (NAPS) algorithm 12 , which has been widely applied to generate hypotheses about how protein structure influences protein function [13][14][15][16][17][18][19][20] . The mathematical parameters of centrality, closeness and betweenness, provide a quantitative framework for the network analysis.…”

Molecular Level Dissection of Critical Spike Mutations in SARS‐CoV‐2 Variants of Concern (VOCs): A Simplified Review

“…Overall the spike glycoprotein has 1273 residues consisting of five regions, including receptor-binding domain (RBD) (residues 319-541), receptor-binding motif (RBM) that binds to human hACE2 (residues 437-508), fusion peptide (residues 788-806), heptad repeat-1 (residues 920-970) and heptad repeat-2 (residues 1163-1202) as shown in Figure 1. [55] All the mutation present in VOC given in the Table 1, are primarily NTD and RBD regions of S1 units. It is worth mentioning that RBD is the key region, within which mutations have been found to impact both infectivity and immunity.…”

XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 Spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants

“…Amino acids 409-417, 462-473 and 530-535 were also found to be protected in the LC-MS/MS analysis although less recognized in the peptide array (Figure 2B). Interestingly, 6 amino acids described to directly interact with human ACE-2 28 are located in these regions.…”