The nonconserved wrapping of conserved protein folds reveals a trend toward increasing connectivity in proteomic networks.

Abstract

Although protein folding domains are generally conserved for function across distant homologous sequences, one crucial structural feature is not conserved: the wrapping of backbone hydrogen bonds, that is, the extent to which they are intramolecularly desolvated and thereby protected from water attack. Extensive data on protein complex interfaces led us to postulate that insufficiently wrapped backbone hydrogen bonds in monomeric domains must be adhesive, and therefore determinants of interactivity, a result that has been experimentally confirmed. Here, we show that the wrapping of certain conserved folds becomes progressively poorer as species diverge in some lineages. This trend is thus concurrent with a progressive enhancement of the interactivity of individual domains sharing the conserved fold. Such increase in interactivity is predicted to impose an "evolutionary brake" on the overall speed of sequence divergence. This phenomenon follows when more and more residues become engaged in protein associations and thus become functionally indispensable. For complete proteomes for which statistically significant structural data are available, scale-free network statistics based solely on the distribution of folding domains, catalogued by their number of wrapping defects, best describe the proteomic connectivity. Thus, the intermolecular connectivity may be effectively used as a measure of species complexity. Our results might contribute to explaining how interactome complexity may be achieved without a dramatic increase in genome size.