Viral Capsid Proteins Are Segregated in Structural Fold Space
Viral capsid proteins assemble into large, symmetrical architectures that are not found in complexes formed by their cellular counterparts. Given the prevalence of the signature jelly-roll topology in viral capsid proteins, we are interested in whether these functionally unique capsid proteins are also structurally unique in terms of folds. To explore this question, we applied a structure-alignment based clustering of all protein chains in VIPERdb filtered at 40% sequence identity to identify distinct capsid folds, and compared the cluster medoids with a non-redundant subset of protein domains in the SCOP database, not including the viral capsid entries. This comparison, using Template Modeling (TM)-score, identified 2078 structural “relatives” of capsid proteins from the non-capsid set, covering altogether 210 folds following the definition in SCOP. The statistical significance of the 210 folds shared by two sets of the same sizes, estimated from 10,000 permutation tests, is less than 0.0001, which is an upper bound on the p-value. We thus conclude that viral capsid proteins are segregated in structural fold space. Our result provides novel insight on how structural folds of capsid proteins, as opposed to their surface chemistry, might be constrained during evolution by requirement of the assembled cage-like architecture. Also importantly, our work highlights a guiding principle for virus-based nanoplatform design in a wide range of biomedical applications and materials science. Viruses are increasingly viewed not as pathogens that parasitize all domains of life, but as useful nanoplatforms for synthetic maneuvers in a wide range of biomedical and materials science applications. One of the most well-known examples of virus-based nanotools developed so far features viral capsules as therapeutic agents, which protect and deliver drug molecules to targeted disease sites in the human body before the drug molecules are released. In order to optimize these nano-designs to best fulfill their purposes, we first have to understand properties of the constitutive building blocks of these viral containers, so as to rationalize and guide the synthetic modification attempts. Based on the observation that viral shells are functionally unique to viruses, we hypothesize that the structure of the building blocks must also be distinct from generic proteins, given that function follows form. Our computational modeling and statistical analysis support this novel hypothesis, and recognize the folded topology of these ‘Lego’ proteins as a differentiating factor to ensure correct geometry, and consequently, proper tiling into the large complex architecture. Our findings highlight an important design principle: efforts on imparting new functionalities to virus templates should restrain from disrupting the fundamental protein fold.