The Viral AlphaFold Database of monomers and homodimers reveals conserved protein folds in viruses of bacteria, archaea, and eukaryotes

Viruses are the most abundant and genetically diverse entities on Earth, yet the functions and evolution of most viral proteins remain poorly understood. Their rapid evolution often obscures evolutionary relationships, limiting the ability to assign functions using sequence-based methods. Although the conservation of protein fold can reveal deep homologies, viral proteins remain underrepresented in structural databases. We address this by clustering viral sequences from RefSeq and predicting the structures of ~27,000 representative proteins using AlphaFold2 to create the Viral AlphaFold Database (VAD). We uncover conserved folds in diverse viruses infecting bacteria, archaea, and eukaryotes. We predict homodimers and make comparisons to the Protein Data Bank, providing data on oligomerization potential. We reveal considerable functional darkness in the viral protein universe and report the discovery and validation of an uncharacterized toxin-antitoxin system. The VAD provides a foundation for exploring viral structure-function relationships, including ancient folds shaping viral interactions across all life.