Multiscale study of interaction between SARS-CoV-2 protein and human receptor complex

Abstract

This study explores the binding mechanism of key binding pockets (S19 Q24 A475 and T500 R357) in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike protein and the Human Angiotensin-Converting Enzyme 2 (hACE2) receptor complex using molecular dynamics (MD) simulations and first-principles calculations. The binding pockets were extracted from the 6LZG protein-protein complex, and the input systems were prepared using CHARMM-GUI for molecular dynamics, PyMOL for structural modifications, and a quantum input generator for first-principles calculations. MD simulations were conducted to assess the stability of the binding pockets and to analyze key interactions, including hydrogen bonding, electrostatic, and van der Waals interactions. Root mean square deviation (RMSD) calculations indicated fluctuations within the system. First-principles calculations, based on density functional theory (DFT) and hybrid functionals, were used to compute the binding energies of residues within the binding pockets, which were found to be negative, suggesting no significant intra-pocket binding. Electronic property analysis revealed that the behavior of key amino acid residues is largely governed by p-orbitals and atomic chemical structure, with minimal influence from crystal symmetry near the Fermi level. Moreover, ethylation of residues A475 was determined to be ineffective in disrupting the interaction between SARS-CoV-2 and the hACE2 receptor.