CROSS-STRAND SIDE-CHAIN INTERACTIONS VERSUS TURN CONFORMATION IN BETA-HAIRPINS

A series of designed peptides has been analyzed by H-1-NMR spectroscop y in order to investigate the influence of cross-strand side-chain int eractions in beta-hairpin formation, The peptides differ in the N-term inal residues of a previously designed linear decapeptide that folds i n aqueous solution into two interconverting beta-hairpin conformations , one with a type I turn (beta-hairpin 4:4) and the other with a type I + G1 beta-bulge turn (beta-hairpin 3:5). Analysis of the conformatio nal behavior of the peptides studied here demonstrates three favorable and two unfavorable cross-strand side-chain interactions for beta-hai rpin formation, These results are in agreement with statistical data o n side-chain interactions in protein beta-sheets. All the peptides in this study form significant populations of the beta-hairpin 3:5, but o nly some of them also adopt the beta-hairpin 4:4. The formation of bet a-hairpin 4:4 requires the presence of at least two favorable cross-st rand interactions, whereas beta-hairpin 3:5 seems to be less susceptib le to side-chain interactions. A protein database analysis of beta-hai rpins 3:5 and beta-hairpins 4:4 indicates that the former occur more f requently than the latter. In both peptides and proteins, beta-hairpin s 3:5 have a larger right-handed twist than beta-hairpins 3:4, so that a factor contributing to the higher stability of beta-hairpin 3:5 rel ative to beta-hairpin 4:4 is due to an appropriate backbone conformati on of the type I + G1 beta-bulge turn toward the right-handed twist us ually observed in protein beta-sheets. In contrast, as suggested previ ously, backbone geometry of the type I turn is not adequate for the ri ght-handed twist. Because analysis of buried hydrophobic surface areas on protein beta-hairpins reveals that beta-hairpins 3:5 bury more hyd rophobic surface area than beta-hairpins 4:4, we suggest that the righ t-handed twist observed in beta-hairpin 3:5 allows a better packing of side chains and that this may also contribute to its higher intrinsic stability.