Interplay between hydrophobic cluster and loop propensity in beta-hairpin formation

Autonomously folding beta -hairpins have recently emerged as powerful tools for elucidating the origins of antiparallel beta -sheet folding preference s. Analysis of such model systems has suggested four potential sources of b eta -sheet stability: (1) the conformational propensity of the loop segment that connects adjacent strands; (2) favorable contacts between side-chains on adjacent strands; (3) interstrand hydrogen bonds; and (4) the intrinsic beta -sheet propensities of the strand residues. We describe the design an d analysis of a series of isomeric 20 residue peptides in which factors (1) -(4) are identical. Differences in beta -hairpin formation within this seri es demonstrate that these four factors, individually, are not sufficient to explain beta -sheet stability. In agreement with the prediction of a simpl e statistical mechanical model for beta -hairpin formation, our results sho w that the separation between the loop segment and an interstrand cluster o f hydrophobic side-chains strongly influences beta -hairpin size and stabil ity, with a smaller separation leading to greater stability. (C) 2001 Acade mic Press.