An in-silico based clinical insight on the effect of noticeable CD4 conserved residues of SARS-CoV-2 on the CD4-MHC-II interactions

Abstract

The study is aimed to unveil the conserved residues of CD4 in the context of its purposeful interaction with MHC-II at the receptor-binding domain (RBD) of SARS-CoV-2 compared with the envelope (Env) glycoprotein (gp) 120 of HIV-1. The paired CD4 conserved residues, including the matched CD4 interacting MHC-II epitopes of the structural viral protein domains, were chosen for the protein modelling using the SWISS-MODEL online server. Energy minimization and structural validation of the modelled viral protein domains, including the CD4 and MHC-II protein were achieved by CHIMERA and PROCHECK-Ramachandran Plot respectively. Protein-protein docking was performed by the HADDOCK online tool. The binding affinity score was measured using the PRODIGY online server.As per our docking report, the Env gp120 of HIV-1 with three identical and three conserved residues of CD4 exhibited the highest binding affinity (-13.9 kcal/mol) with MHC-II than the second-highest RBD-S1-SARS-CoV-2 (-12.5 kcal/mol) with three identical and a single conserved residue of CD4. With a noticeable single salt bridge formation identified at the interacting residues Lys305 (of Env gp120-HIV-1) and Glu139 (of MHC-II); the Env gp120 interaction with MHC-II occupied the crucial His144 and Glu194 (salt-bridge) interacting residues of CD4 with the measured buried surface area 2554.8±40.8 Å 2 . Similarly, the RBD-S1-SARS-CoV-2-MHC-II complex showed two salt bridge formations at the residue sites: 1) Arg567 (of SARS-CoV-2)-Glu194 (of MHC-II) 2) 2) Asp568(of SARS-CoV-2)-Arg165 (of MHC-II) with the increased buried surface area of 1910.9±97.1 Å 2 over the SARS-CoV score 1708.2±50.8 Å 2 ; that camouflaged all crucial CD4 interacting residues of MHC-II. In conclusion, the noticeable conserved residues of CD4 at the RBD-S1 sites of SARS-CoV-2 could interrupt the aspired CD4-MHC-II interactions of adaptive immune activation.