Glycan shielding and epitope reorganization drive sotrovimab resistance in SARS-CoV-2 Omicron variants.

The rapid antigenic evolution of the SARS-CoV-2 spike protein has progressively eroded the efficacy of therapeutic monoclonal antibodies, including sotrovimab. Omicron BA.1 and BA.2 variants exhibit markedly reduced neutralization potency; however, the molecular and energetic mechanisms underlying this resistance, particularly the contribution of glycan-mediated epitope reorganization, remain insufficiently resolved. Here, we elucidate how BA.1 and BA.2 mutations reshape the structural dynamics, interfacial energetics, and glycan-mediated epitope masking in the sotrovimab-receptor-binding domain (RBD) complex. Extensive molecular dynamics simulations (1.5 μs all-atom; 15 μs coarse-grained) revealed that Omicron-specific mutations induce pronounced conformational plasticity within the RBD, accompanied by local secondary-structure destabilization and enhanced dynamic heterogeneity relative to the wild-type complex. These changes weaken sotrovimab-stabilizing hydrogen-bond networks and disrupt persistent interfacial contacts critical for sotrovimab recognition. Free-energy landscape analyses demonstrated a shift toward less favorable binding conformational states in both BA.1 and BA.2, consistent with reduced complex stability. Dynamic cross-correlation analysis further demonstrated progressive loss of coordinated long-range motions and fragmentation of the sotrovimab-RBD communication network, most prominently in BA.2. Binding free-energy decomposition further revealed substantial losses in overall affinity and pronounced redistribution of residue-level energetic contributions at the sotrovimab-RBD interface. Notably, mutation-induced reorientation and increased mobility of the conserved N343-linked glycan enhances steric shielding of the sotrovimab epitope and perturbs key glycan-mediated stabilizing interactions, amplifying sotrovimab-escape despite limited direct epitope mutation. Together, these results establish that sotrovimab resistance in Omicron BA.1 and BA.2 arises from a synergistic interplay of RBD conformational destabilization, weakened interfacial energetics, disrupted dynamic coupling, and glycan-mediated epitope shielding.