Characterization and Prediction of Viral Capsid Geometries

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Viruses are the most abundant biological entity on the planet and play a crucial role in the evolution of organisms and the biogeochemistry of Earth. Closely related viruses, however, can have very dissimilar genomes, complicating integration of knowledge acquired from the study of independent viruses, and limiting prediction of the characteristics and potential threats of emerging viruses. Viruses, however, conserve a few structural properties that could help circumvent this problem. Most viruses store their infective genetic material in a protein shell called a capsid. The capsid self-assembles from multiple copies of the same (or similar) proteins, and most capsids display icosahedral symmetry. This architecture optimizes the interaction of proteins and the volume available to store the viral genetic information. This research project hypothesizes that viruses have evolved a limited set of replication strategies to specialize and exploit the reduced number of geometrical templates capable of forming icosahedral capsids. This, in turn, may have constrained the number of three-dimensional configurations adopted by capsid proteins, providing a mechanistic rationale for the existence of viral structural lineages. This hypothesis will be tested by analyzing and comparing hundreds of viruses from multiple different viral families using novel mathematical methods. Confirming this hypothesis will offer a quantitative framework to study viral evolution and open the door to design of generic antiviral strategies targeting viruses in the same structural lineage.Only ten protein folds have been identified among major capsid proteins of viruses that form icosahedral capsids. These folds define viral lineages that group viruses that can be genetically unrelated and infect hosts from different domains of life. This limited number of folds contrasts with the vast genetic diversity of viruses. The existence of these folds across the virosphere, however, remains unknown. Here, it is hypothesized that there is a direct relationship between the viral replication strategy of each viral lineage, the icosahedral lattice of the capsid, and the fold of capsid proteins. The hypothesis will be tested by developing a database that will include the viral replication, protein fold, and capsid lattice of five hundred viruses that have been reconstructed at high or medium molecular resolution. Voronoi tessellations and protein-protein interaction lattices will be obtained to identify computationally the icosahedral lattice associated to each virus. Additionally, molecular measurements of the reconstructed capsids will be obtained to establish allometric relationships for at least one viral lineage, facilitating the prediction of icosahedral capsid properties from genomic information. The new icosahedral framework will be also extended to obtain new sets of elongated capsids, which represent the second most abundant type of capsid. The methods will be disseminated online for use by viral structure researchers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.