Structural features can be unconserved in proteins with similar folds. An analysis of side-chain to side-chain contacts secondary structure and accessibility.
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 type C having only 3D structural similarity. Within proteins having little or no sequence similarity (types B and C), structural features frequently had a degree of conservation comparable to dissimilar 3D structures. Despite similar protein folds, as few as 30% of residues within similar protein 3D structures can form a common core. RMS deviations on core C alpha atoms can be as high as 3.2 A. Similar protein structures can have secondary structure identities as low as 41%, which is equivalent to that expected by chance. By defining three categories of amino acid accessibility (buried, half buried and exposed), some similar protein 3D structures have as few as 30% of positions in the same category, making them indistinguishable from pairs of dissimilar protein structures. Similar structures can also have as few as 12% of common side-chain to side-chain contacts, and virtually no similar energetically favourable side-chain to side-chain interactions. Complementary changes are defined as structurally equivalent pairs of interacting residues in two structures with energetically favourable but different side-chain interactions. For many proteins with similar three-dimensional structures, the proportion of complementary changes 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 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 (e.g. accessibility, side-chain to side-chain contacts, etc.) are often unconserved within weakly similar (i.e. type B and C) protein 3D structures. Little difference was found between type B and 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 the requirements for burial of hydrophobic residues and exposure of polar residues, rather than specific residue-residue interactions that determine how well a particular sequence adopts a particular fold.(ABSTRACT TRUNCATED AT 400 WORDS)
University of Oxford, Laboratory of Molecular Biophysics, U.K.
R B
RB
Russell
G J
GJ
Barton
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment