Probing the influence of sequence‐dependent interactions upon α‐helix stability in alanine‐based linear peptides

Abstract

The observation that short, linear alanine-based polypeptides form stable alpha-helices in aqueous solution has allowed the development of well-defined experimental systems with which to study the influence of amino acid sequence upon the stability of secondary structure. We have performed detailed conformational searches upon six alanine-based peptides in order to rationalize the observed variation in the alpha-helical stability in terms of side-chain-backbone and side-chain-side-chain interactions. Although a simple, gas-phase, potential model was used to obtain the conformational energies for these peptides, good agreement was obtained with experiment regarding their relative alpha-helical stabilities. Our calculations clearly indicate that valine, isoleucine, and phenylalanine residues should destabilize the alpha-helical conformation when included within alanine-based peptides because of energetically unfavorable side-chain-backbone interactions, which tend to result in the formation of regions of 3(10)-helix. In the case of valine, the destabilization most probably arises from entropic effects as the isopropyl side chain can assume more orientations in the 3(10)-helical form of the peptide. A detailed examination of very short-range interactions in these peptides has also indicated that an interaction, involving fewer than five consecutive residues, whose stabilizing effect reinforces that of the (i, i + 4) hydrogen bond may be the basis of the requirement for increased nucleation (sigma) and propagation parameters (s) required by Zimm-Bragg theory to predict the alpha-helical content for compounds in this class of short peptides. Our calculations complement recent work using modified Zimm-Bragg and Lifson-Roig theories of the helix-coil transition, and are consistent with molecular dynamics simulations upon linear peptides in aqueous solution.