# Subtle Changes at the RBD/hACE2 Interface During SARS-CoV-2 Variant Evolution: A Molecular Dynamics Study

## TL;DR

This study uses molecular dynamics to explore how SARS-CoV-2 variants, especially Omicron, interact differently with human cells compared to earlier variants like Delta.

## Contribution

The study identifies subtle molecular changes in Omicron variants that may enhance their binding stability and persistence.

## Key findings

- Omicron variants show stronger electrostatic and hydrophobic interactions at the RBD/hACE2 interface.
- The S375F mutation in Omicron is linked to increased binding stability.
- Contact networks reveal dynamic changes that may explain Omicron's dominance over Delta.

## Abstract

The SARS-CoV-2 Omicron variants show different behavior compared to the previous variants, especially with respect to the Delta variant, which promotes a lower morbidity despite being much more contagious. In this perspective, we performed molecular dynamics (MD) simulations of the different spike RBD/hACE2 complexes corresponding to the WT, Delta and four Omicron variants. Carrying out a comprehensive analysis of residue interactions within and between the two partners allowed us to draw the profile of each variant by using complementary methods (PairInt, hydrophobic potential, contact PCA). PairInt calculations highlighted the residues most involved in electrostatic interactions, which make a strong contribution to the binding with highly stable interactions between spike RBD and hACE2. Apolar contacts made a substantial and complementary contribution in Omicron with the detection of two hydrophobic patches. Contact networks and cross-correlation matrices were able to detect subtle changes at point mutations as the S375F mutation occurring in all Omicron variants, which is likely to confer an advantage in binding stability. This study brings new highlights on the dynamic binding of spike RBD to hACE2, which may explain the final persistence of Omicron over Delta.