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

The observation that short, linear alanine‐based polypeptides form stable α‐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 α‐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 α‐helical stabilities. Our calculations clearly indicate that valine, isoleucine, and phenylalanine residues should destabilize the α‐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 (σ) and propagation parameters ( s ) required by Zimm–Bragg theory to predict the α‐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. © 1993 John Wiley & Sons, Inc.