FoldaVirus, a knowledge-based icosahedral capsid prediction tool using AlphaFold.

Abstract

Coat protein (CP) tertiary structures and their capsid organization of spherical viruses are generally well conserved within each virus family. While AlphaFold successfully predicts the tertiary structures of individual CPs, their association to form proper quaternary assemblies cannot be easily accomplished. Here, we report a generalized methodology and an associated web-based utility (https://foldavirus.org) that combines AlphaFold predictions of CPs with the knowledge on corresponding icosahedral architectures (e.g., <i>T</i> = 1, 3, 4…) based on the known structures from the related virus family to generate associated capsids. The resulting assemblies are relaxed using Amber energy minimization to relieve any steric clashes at the intersubunit interfaces. Significantly, the capsid models are validated by calculating robust Mahalanobis distance using the residue annotations categorized as interface, core, and surface amino acids with respect to those observed in the experimentally determined structures from the corresponding virus family. Given the amino acid sequence of CP(s), we successfully generated capsids up to <i>T</i> = 9 icosahedral symmetry, including those of picornaviruses that display pseudo-<i>T</i> = 3 symmetry comprising VP1-VP4. As the number of currently available CP sequences are 2 to 3 orders of magnitude larger than the experimentally determined 3D-structures, this approach bridges the huge gap that exists between the sequence and structural space of viruses.