Topology-Aware Modeling of the Full Genome Reveals Stability Determinants in a Small Naked Virus

Icosahedral viruses, despite offering high-resolution capsid structures through cryo-electron microscopy and X-ray crystallography, present a major obstacle: their genomes do not obey icosahedral symmetry and are thus averaged out during standard reconstruction procedures, leaving genome topology largely unresolved.

Computational modeling offers a complementary avenue, but existing approaches often rely on simplified polymer representations that fail to capture sequence-specific features and the extreme compaction observed in small DNA viruses. Here, we focus on Porcine Circovirus type 2 (PCV2), a member of the <i>Circoviridae</i> family and one of the smallest autonomous mammalian viruses, which packages a circular ∼1.7 kb single-stranded DNA genome into a ∼20 nm T = 1 icosahedral capsid at one of the highest DNA packing densities found in nature.