Identification of temperature-insensitive residues in regulating SARS-CoV-2 variants-human ACE2 interaction-a study of molecular dynamics simulation.

Abstract

The COVID-19 pandemic remains a global health crisis, with successive SARS-CoV-2 variants exhibiting enhanced transmissibility and immune evasion. Notably, the Omicron variant harbors extensive mutations in the spike protein's receptor-binding domain (RBD), altering viral fitness. While temperature is a critical environmental factor modulating viral stability and transmission, its molecular-level effects on variant-specific RBD-human angiotensin-converting enzyme 2 (hACE2) interactions remain underexplored. Here, we employed all-atom molecular dynamics (MD) simulations to investigate temperature-dependent conformational dynamics of four major variants (alpha, beta, delta, and omicron) complexed with hACE2 at three temperatures (190 K, 250 K, and 310 K). Our analyses revealed two temperature-insensitive residues (K417N and E484K/A) in beta and omicron variants that maintain stable conformational states between 250 K and 310 K, contrasting sharply with temperature-dependent fluctuations observed in alpha and delta variants. These residues function as an allosteric converter, modulating interfacial interactions through temperature-regulated electrostatic and hydrophobic forces. Furthermore, we identified key "effector" residues (Q493, Y501 in beta; F486, R498 in omicron) that mediate temperature-dependent binding affinity changes. Our findings provide mechanistic insights into variant-specific environmental adaptation and propose novel targets for broad-spectrum therapeutic design.