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J Mol Biol. 2015 Nov 6;427(22):3613-3624. doi: 10.1016/j.jmb.2015.09.008. Epub 2015 Sep 12.

Protein-Protein Interfaces in Viral Capsids Are Structurally Unique.

Author information

1
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109-2218, USA. Electronic address: sscheng@umich.edu.
2
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109-2218, USA; Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA; Biophysics Program, University of Michigan, Ann Arbor, MI 48109-1055, USA. Electronic address: brookscl@umich.edu.

Abstract

Viral capsids exhibit elaborate and symmetrical architectures of defined sizes and remarkable mechanical properties not seen with cellular macromolecular complexes. Given the uniqueness of the higher-order organization of viral capsid proteins in the virosphere, we explored the question of whether the patterns of protein-protein interactions within viral capsids are distinct from those in generic protein complexes. Our comparative analysis involving a non-redundant set of 551 inter-subunit interfaces in viral capsids from VIPERdb and 20,014 protein-protein interfaces in non-capsid protein complexes from the Protein Data Bank found 418 generic protein-protein interfaces that share similar physicochemical patterns with some protein-protein interfaces in the capsid set, using the program PCalign we developed for comparing protein-protein interfaces. This overlap in the structural space of protein-protein interfaces is significantly small, with a p-value <0.0001, based on a permutation test on the total set of protein-protein interfaces. Furthermore, the generic protein-protein interfaces that bear similarity in their spatial and chemical arrangement with capsid ones are mostly small in size with fewer than 20 interfacial residues, which results from the relatively limited choices of natural design for small interfaces rather than having significant biological implications in terms of functional relationships. We conclude based on this study that protein-protein interfaces in viral capsids are non-representative of patterns in the smaller, more compact cellular protein complexes. Our finding highlights the design principle of building large biological containers from repeated, self-assembling units and provides insights into specific targets for antiviral drug design for improved efficacy.

KEYWORDS:

biological containers; capsid shells; drug specificity; protein–protein interaction; structural comparison

PMID:
26375252
PMCID:
PMC4624513
DOI:
10.1016/j.jmb.2015.09.008
[Indexed for MEDLINE]
Free PMC Article

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