Relationship between side chain structure and 14-helix stability of β3-peptides in water

Abstract

Folded polymers are used in Nature for virtually every vital process. Nonnatural folded polymers, or foldamers, have the potential for similar versatility, and the design and refinement of such molecules is of considerable current interest. Here we report a complete and systematic analysis of the relationship between side chain structure and the 14-helicity of a well-studied class of foldamers, β3-peptides, in water. Our experimental results (1) verify the importance of macrodipole stabilization for maintaining 14-helix structure, (2) provide comprehensive evidence that β3- amino acids branched at the first side chain carbon are 14-helix-stabilizing, (3) suggest a novel role for side chain hydrogen bonding as an additional stabilizing force in β3-peptides containing β3- homoserine or β3-homothreonine, and (4) demonstrate that diverse functionality can be incorporated into a stable 14-helix. Gas- and solution-phase calculations and Monte Carlo simulations recapitulate the experimental trends only in the context of oligomers, yielding insight into the mechanisms behind 14-helix folding. The 14-helix propensities of β3-amino acids differ starkly from the α-helix propensities of analogous α-amino acids. This contrast informs current models for α-helix folding, and suggests that 14-helix folding is governed by different biophysical forces than is α-helix folding. The ability to modulate 14-helix structure through side chain choice will assist rational design of 14-helical β-peptide ligands for macromolecular targets.