Jacchieri S G, Richards N G
Department of Chemistry, University of Florida, Gainesville 32611.
Biopolymers. 1993 Jun;33(6):971-84. doi: 10.1002/bip.360330613.
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.
短的、基于丙氨酸的线性多肽在水溶液中形成稳定的α-螺旋这一现象，使得人们能够开发出定义明确的实验系统，用以研究氨基酸序列对二级结构稳定性的影响。我们对六种基于丙氨酸的肽进行了详细的构象搜索，以便从侧链-主链和侧链-侧链相互作用的角度，合理解释观察到的α-螺旋稳定性变化。尽管使用了一个简单的气相势能模型来获得这些肽的构象能量，但在它们相对的α-螺旋稳定性方面，计算结果与实验结果取得了良好的一致性。我们的计算清楚地表明，当缬氨酸、异亮氨酸和苯丙氨酸残基包含在基于丙氨酸的肽中时，由于能量上不利的侧链-主链相互作用，会使α-螺旋构象不稳定，这种相互作用往往会导致形成3(10)-螺旋区域。就缬氨酸而言，不稳定最可能源于熵效应，因为异丙基侧链在肽的3(10)-螺旋形式中可以有更多的取向。对这些肽中非常短程相互作用的详细研究还表明，一种涉及少于五个连续残基的相互作用，其稳定作用增强了(i, i + 4)氢键的稳定作用，这可能是齐姆-布拉格理论预测这类短肽化合物α-螺旋含量所需增加成核(σ)和延伸参数(s)的要求的基础。我们的计算补充了最近使用修正的螺旋-卷曲转变的齐姆-布拉格理论和利夫森-罗伊格理论所做的工作，并且与水溶液中线性肽的分子动力学模拟结果一致。
