From sites to structure to serology: a roadmap for structure-aware molecular evolution of antigenically evolving viruses

The genomic deluge has pushed viral molecular evolution into a site-resolved era. For antigenically evolving viruses such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), dense genomic sampling now supports mutation-annotated phylogenies and per-site estimates of mutation and substitution processes. These data highlight strong effects of sequence context, genomic region, RNA structure, and protein-level constraints that are blurred by classic uniform substitution models. In parallel, accurate structure prediction and emerging structure-aware phylogenetic and machine-learning approaches provide practical ways to map mutations onto three-dimensional constraints, identify structurally plausible escape routes, and interpret evolutionary rate variation through solvent exposure, packing, stability, glycosylation, receptor-binding interfaces, and epitope geometry. Finally, antigenic cartography translates some forms of genetic change into an epidemiologically meaningful phenotype-antigenic distance-while predictive modeling increasingly enables sequence-to-antigenicity inference for variants that have not yet been tested experimentally. Here, we outline a practical framework linking sites, structure, and serology for viruses in which antigenic evolution is a major component of immune escape and lineage turnover; highlight why genetic and antigenic "clocks" can diverge; and discuss how integrating genomic surveillance data, phylogenetics, structural analysis, and predictive modeling could support more prospective variant assessment and improved vaccine and therapeutic design.