Structural dynamics and energetic basis of conserved ACE2 binding across SARS-CoV-2 variants.

Abstract

The SARS-CoV-2 receptor-binding domain (RBD) mediates viral entry through binding to the human angiotensin-converting enzyme 2 (ACE2) receptor. Since the emergence of SARS-CoV-2, numerous variants have accumulated mutations within the RBD, particularly among Omicron sublineages. Here, molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations were used to investigate RBD-ACE2 interactions across SARS-CoV-2 variants, including Alpha, Gamma, Delta, Epsilon, Kappa, Mu, and Omicron subvariants BA.1, BA.2, BA.3, BA.4/BA.5, BA.2.12.1, BA.2.75, BA.4.6, BA.5.9, XBB.1.5, XBB.1.16, EG.5, BA.2.86, JN.1, NB.1.8.1, and XFG. Global structural properties, including backbone stability, compactness, and solvent accessibility, were highly conserved across variants. In contrast, residue-level flexibility was concentrated within the receptor-binding motif (RBM), with Omicron subvariants exhibiting greater heterogeneity than earlier variants. Essential dynamics analysis indicated that variant evolution primarily modulates the extent of conformational sampling along a conserved dominant mode of motion. Hydrogen bond analysis showed that substitutions at residue 493 altered local RBD-ACE2 hydrogen-bonding networks while preserving a conserved set of interface-stabilising interactions. MM-PBSA analysis demonstrated that binding was primarily driven by favourable electrostatic interactions localised to key RBM residues, particularly in early Omicron subvariants. However, these gains were largely offset by opposing polar solvation penalties, resulting in only modest variation in predicted ACE2 binding affinity. Together, these findings indicate that SARS-CoV-2 evolution maintains RBD-ACE2 binding through compensatory structural and energetic changes despite extensive mutation of the RBD.

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