Structural features can be unconserved in proteins with similar folds
An analysis of side-chain to side-chain contacts, secondary structure and accessibility

Robert B. Russell & Geoffrey J. Barton
J. Mol. Biol., 244,332-350, 1994.


Side-chain to side-chain contacts, accessibility, secondary structure and RMS deviation were compared within 607 pairs of proteins having similar three-dimensional (3D) structures. Three types of protein 3D structural similarities were defined: type A having sequence and usually functional similarity; type B having functional, but no sequence similarity; and typeChaving only 3D structural similarity. Within proteins having little or no sequence similarity (typesBand C), structural features were frequently found to be unconserved when compared to dissimilar 3D structures.

Despite similar protein folds, it was found that as few as30 \%of residues within similar protein 3D structures form a common core. RMS deviations on core \Cal atoms were found to be as high as3.2 angstroms. Similar protein structures were found to have secondary structure identities as low as41 \%, which is equal to that expected by chance. By defining three categories of amino acid accessibility (buried, half buried and exposed), some similar protein 3D structures were found to have less than30 \%of positions in the same category, making them indistinguishable from pairs of dissimilar protein structures. Similar structures were also found to share as few as12 \%of side-chain to side-chain contacts, and virtually no similar energetically favourable side-chain to side-chain interactions. In addition, the proportion of complementary changes (structurally equivalent pairs of interacting residues in two structures with energetically favourable but different side-chain interactions) for many proteins that share similar three-dimensional structures is near to that expected by chance, suggesting that many similar structures have fundamentally different stabilising interactions.

All of the results suggest that proteins having similar 3D structures can have little in common apart from a scaffold of common core secondary structures. This has profound implications for methods of protein fold detection, since many of the properties assumed to be conserved across similar protein 3D structures (eg. accessibility, side-chain to side-chain contacts, etc.) are often unconserved within weakly similar (ie. typeBand C) protein 3D structures. Little difference was found between typeBand C similarities suggesting that the structure of similar proteins can evolve beyond recognition even when function is conserved.

Our findings suggest that it is more general features of protein structure, such as having hydrophobic residues buried in the core of proteins, and polar residues on the surface, rather than particular residue-residue interactions that determine how well a particular sequence adopts a particular fold. If detection of similar folds having little in common outside of their core secondary structures is to become a reality, efforts should concentrate on such general principles, and on methods for modelling large loop regions that are likely to differ between similar 3D structures.