Host-Associated Binding Patterns in Predicted Structural Models of Circovirus Capsid-Importin Complexes

The nuclear entry of the capsid protein is a critical step in the life cycle of circoviruses, but whether capsid proteins from different circoviruses differ in their importin interactions remained unclear. Here, we modeled 298 unique circovirus capsid protein-importin pairs using AlphaFold 3. After conformational clustering and ZDOCK concordance filtering, 603 representative interfaces were retained for analysis. We extracted ΔiG values, interface features, and nuclear localization signal (NLS)-specific interface properties by PDBePISA and analyzed them with statistical tests. Capsid protein (Cap)-importin-9 (IPO9) complexes showed the lowest mean ΔiG among all tested circoviruses, identifying IPO9 as a candidate broadly interacting importin among the viruses examined. Across all host classes, Cap-importin β complexes showed a lower mean ΔiG than Cap-importin α or Cap-transportin complexes. Predicted ΔiG patterns differed across host classes, with distinct profiles for avian, mammalian, and fish circoviruses. Predicted ΔiG patterns and NLS interface features, including basic residue ratio, interface occupancy, and net charge, differed across avian, mammalian, and fish circoviruses. Together, these results provide a set of testable predictions regarding circovirus Cap-importin interfaces and highlight the predicted NLS interface as a region for further investigation.