Analysis of protein sequence/structure similarity relationships

Current analyses of protein sequence/structure relationships have focused on expected similarity relationships for structurally similar proteins. To survey and explore the basis of these relationships, we present a general sequence/structure map that covers all combinations of similarity/dissimilarity relationships and provide novel energetic analyses of these relationships. To aid our analysis, we divide protein relationships into four categories: expected/unexpected similarity (S and S^?) and expected/unexpected dissimilarity (D and D^?) relationships. In the expected similarity region S, we show that trends in the sequence/structure relation can be derived based on the requirement of protein stability and the energetics of sequence and structural changes. Specifically, we derive a formula relating sequence and structural deviations to a parameter characterizing protein stiffness; the formula fits the data reasonably well, We suggest that the absence of data in region S^? (high structural but low sequence similarity) is due to unfavorable energetics. In contrast to region S, region D^? (high sequence but low structural similarity) is well-represented by proteins that can accommodate large structural changes. Our analyses indicate that there are several categories of similarity relationships and that protein energetics provide a basis for understanding these relationships.