Control of Hairpin Formation via Proline Configuration in Parallel β-Sheet Model Systems

Abstract

The simplest strategy for creation of parallel β-sheet model systems is to link adjacent peptide strands via their N-termini or via their C-termini. This connectivity requires unnatural linking segments. We describe dipeptide mimics that can serve as N-to-N or C-to-C linkers, and we demonstrate their efficacy by conformational analysis of tetrapeptide analogues in chloroform. The tetrapeptide analogues can adopt strand−loop−strand (“hairpin”) conformations in which the residues at each end, l-valine and l-leucine, engage in parallel sheet hydrogen bonding interactions. Our linkers contain proline residues, to impart a preferred local twist. We show that linkers containing d-proline promote parallel sheet interactions between the strand l-residues, while linkers containing l-proline do not promote parallel sheet interactions. The preference for one linker twist is presumably related to the right-handed twist displayed by strands in protein β-sheets (parallel and antiparallel); analogous linker twist preferences have been observed in antiparallel β-sheet model systems.