Analysis of proteins commonly requires the partition of their structure into regions such as the surface, interior, or interface. Despite the frequent use of such categorization, no consensus definition seems to exist. This study thus aims at providing a definition that is general, is simple to implement, and yields new biological insights. This analysis relies on 397, 196, and 701 protein structures from Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens, respectively, and the conclusions are consistent across all three species. A threshold of 25% relative accessible surface area best segregates amino acids at the interior and at the surface. This value is further used to extend the core-rim model of protein-protein interfaces and to introduce a third region called support. Interface core, rim, and support regions contain similar numbers of residues on average, but core residues contribute over two-thirds of the contact surface. The amino acid composition of each region remains similar across different organisms and interface types. The interface core composition is intermediate between the surface and the interior, but the compositions of the support and the rim are virtually identical with those of the interior and the surface, respectively. The support and rim could thus "preexist" in proteins, and evolving a new interaction could require mutations to form an interface core only. Using the interface regions defined, it is shown through simulations that only two substitutions are necessary to shift the average composition of a 1000-Å(2) surface patch involving ∼28 residues to that of an equivalent interface. This analysis and conclusions will help understand the notion of promiscuity in protein-protein interaction networks.
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