Abstract
The role of N‐terminus diproline segments in facilitating helical folding in short peptides has been investigated in a set of model hexapeptides of the type Piv‐Xxx‐Yyy‐Aib‐Leu‐Aib‐Phe‐OMe (Piv, pivaloyl). Nine sequences have been investigated with the following N‐terminus dipeptide segments: ^D^Pro‐Ala (4) and Pro‐ΨPro (5, Ψ, pseudoproline), Ala‐Ala (6), Ala‐Pro (7), Pro‐Ala (8), Aib‐Ala (9), Ala‐Aib (10). The analog sequences Piv‐Pro‐Pro‐Ala‐Leu‐Aib‐Phe‐OMe (2) and Piv‐Pro‐Pro‐Ala‐Aib‐Ala‐Aib‐OMe (3) have also been studied. Solid state conformations have been determined by X‐ray crystallography for peptides 4, 6, and 8 and compared with the previously determined crystal structure of peptide 1 (Boc‐Pro‐Pro‐Aib‐Leu‐Aib‐Val‐OMe); (Rai et al., JACS 2006, 128, 7916–7928). Peptides 1 and 6 adopt almost identical helical conformations with unfolding of the helix at the N‐terminus Pro (1) residue. Peptide 4 reveals the anticipated ^D^Pro‐Ala type II' β‐turn, followed by a stretch of 3~10~‐helix. Peptide 8 adopts a folded conformation stabilized by four successive 4→1 intramolecular hydrogen bonds. Ala (2) adopts an α~L~ conformation, resulting in a type II β‐turn conformation followed by a stretch of 3~10~‐helix. Conformational properties in solution were probed using solvent perturbation of NH chemical shifts which permit delineation of hydrogen bonded NH groups and nuclear Overhauser effects (NOEs) between backbone protons, which are diagnostic of local residue conformations. The results suggest that, continuous helical conformations are indeed significantly populated for peptides 2 and 3. Comparison of the results for peptides 1 and 2, suggest that there is a significant influence of the residue that follows diproline segments in influencing backbone folding. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 360–370, 2010.
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