An incipient 3₁₀ helix in Piv-Pro-Pro-Ala-NHMe as a model for peptide folding

Abstract

The molecular mechanism of helix nucleation in peptides and proteins is not yet understood and the question of whether sharp turns in the polypeptide backbone serve as nuclei for protein folding has evoked controversy. A recent study of the conformation of a tetrapeptide containing the stereochemically constrained residue α-aminoisobutyric acid, both in solution and the solid state, yielded a structure consisting of two consecutive β-turns, leading to an incipient 3₁₀ helical conformation. This led us to speculate that specific tri- and tetra-peptide sequences may indeed provide a helical twist to the amino-terminal segment of helical regions in proteins and provide a nucleation site for further propagation. The transformation from a 3₁₀ helical structure to an α-helix should be facile and requires only small changes in the φ and ψ conformational angles and a rearrangement of the hydrogen bonding pattern. If such a mechanism is involved then it should be possible to isolate an incipient 3₁₀ helical conformation in a tripeptide amide or tetrapeptide sequence, based purely on the driving force derived from short-range interactions. We have synthesised and studied the model peptide pivaloyl-Pro-Pro-Ala-NHMe (compound I) and provide here spectroscopic evidence for a 3₁₀ helical conformation in compound I.