The Mechanism of β-Hairpin Formation

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Abstract
β-Hairpins constitute an important class of connecting protein secondary structures. Several groups have postulated that such structures form early in the folding process and serve to nucleate the formation of extended β-sheet structures. Despite the importance of β-hairpins in protein folding, little is known about the mechanism of formation of these structures. While it is well established that there is a complex interplay between the stability of a β-hairpin and loop conformational propensity, loop length, and the formation of stabilizing cross-strand interactions (H-bonds and hydrophobic interactions), the influence of these factors on the folding rate is poorly understood. Peptide models provide a simple framework for exploring the molecular details of the formation of β-hairpin structures. We have explored the fundamental processes of folding in two linear peptides that form β-hairpin structures, having a stabilizing hydrophobic cluster connected by loops of differing lengths. This approach allows us to evaluate existing models of the mechanism of β-hairpin formation. We find a substantial acceleration of the folding rate when the connecting loop is made shorter (i.e., the hydrophobic cluster is moved closer to the turn). Analysis of the folding kinetics of these two peptides reveals that this acceleration is a direct consequence of the reduced entropic cost of the smaller loop search.