Structural conservation of predicted Andes virus postfusion glycoprotein C models across three decades

Andes virus (ANDV) is a hantavirus capable of human-to-human transmission and has been associated with hantavirus cardiopulmonary syndrome. Although mutations associated with transmission have been reported, how the postfusion glycoprotein C (Gc) structure has evolved during long-term human circulation remains poorly understood. Here, we examined structural patterns among predicted postfusion ANDV Gc trimer models spanning 1996 to 2026, using integrated network biology, structural bioinformatics, and machine learning approaches. Phylogenetic network analysis identified the M segment as the most topologically prominent among the three genomic segments, which motivated our subsequent focus on the postfusion Gc protein. High-confidence postfusion Gc trimer models were generated for nine isolates, and pairwise structural comparisons were performed using RMSD. Across all pairwise comparisons, the predicted postfusion Gc models were structurally similar overall, with no significant correlation between temporal distance and structural divergence. Hierarchical clustering and a multidimensional scaling (MDS)-derived structural similarity network grouped six of the nine models (1996, 2010, 2016, 2018, 2022, and 2024) together, while the 1999 and 2026 models formed a distinct pair with a near-identical predicted structure to one another, and the 2002 model occupied a separate position. Taken together, the predicted postfusion Gc models suggest a structurally constrained fusogenic domain that may tolerate only limited conformational excursions over three decades of human circulation. However, we wish to emphasize that the finer-grained groupings observed within this conserved range remain exploratory and would require independent evolutionary or functional evidence to confirm biological significance.