The Relationship Between Protein Structure and Function: A Comprehensive Survey Focusing on Enzymes

For most proteins in the genome databases, function is predicted via sequence comparison. In spite of the popularity of this approach, the extent to which it can be reliably applied is unknown. We address this issue by systematically investigating the relationship between protein function and structure. We focus initially on enzymes classified by the Enzyme Commission EC and relate these to structurally classified proteins in the SCOP database. We find that the major SCOP fold classes have different propensities to carry out certain broad categories of functions. For instance, alphabeta folds are disproportionately associated with enzymes, especially transferases and hydrolases, and all-alpha and small folds with non-enzymes, while alpha beta folds have an equal tendency either way. These observations for the database overall are largely true for specific genomes. We focus, in particular, on yeast, analyzing it with many classifications in addition to SCOP and EC i.e. COGs, CATH, MIPS, and find clear tendencies for fold-function association, across a broad spectrum of functions. Analysis with the COGs scheme also suggests that the functions of the most ancient proteins are more evenly distributed among different structural classes than those of more modern ones. For the database overall, we identify the most versatile functions, i.e. those that are associated with the most folds, and the most versatile folds, associated with the most functions. The two most versatile enzymatic functions hydro-Ivases and O-glycosyl glucosidases are associated with seven folds each. The ve most versatile folds TIM-barrel, Rossmann, ferredoxin, alpha-beta hydrolase, and P-loop NTP hydrolase are all mixed alpha-beta structures. They stand out as generic scaffolds, accommodating from six to as many as 16 functions for the exceptional TIM-barrel.