A stereoelectronic effect on turn formation due to proline substitution in elastin-mimetic polypeptides
A stereoelectronic effect on turn formation due to proline substitution in elastin-mimetic polypeptides
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DOI：
10.1021/ja054105j
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发表时间：
2005-12-28
影响因子：
15
通讯作者：
Conticello, VP
中科院分区：
文献类型：
--
作者：
Kim, W;McMillan, RA;Conticello, VP
立体电子效应已被确定为促进胶原样肽序列构象稳定性的因素。为了评估这些因素在其他蛋白质结构背景下的相关性，制备了三个多肽序列，其中这些序列来源于蛋白质材料弹性蛋白的典型重复单元（Val-Pro-Gly-Val-Gly）。这些模拟弹性蛋白的多肽，弹性蛋白1、弹性蛋白2和弹性蛋白3，分别在弹性蛋白重复序列的第二个位置包含(2S)-脯氨酸、(2S,4S)-4-氟脯氨酸和(2S,4R)-4-氟脯氨酸。对这三种多肽的量热和光谱研究表明，取代脯氨酸残基的掺入对相应弹性蛋白肽的自组装有显著影响。相对于亲本多肽，(2S,4R)-4-氟脯氨酸的存在降低了相变温度，增加了II型β -转种群，而(2S,4S)-4-氟脯氨酸的存在则起到相反的作用。这些结果表明，立体电子效应可以增强或阻碍模拟弹性蛋白多肽的自组装，这取决于脯氨酸类似物对相变以上五肽结构重复序列中β -转构象的能量学的影响。采用密度泛函理论（DFT）对弹性蛋白重复单元（var -Pro- gly - var - gly）的转弯形成残基对应的模型肽段（MeCO-Xaa-Gly-NHMe） （Xaa = Pro， 4S-F-Pro或4R-F-Pro）衍生的三种可能的转弯类型(β （I)-, β (II)-和反γ -转弯）进行建模。这些计算结果与模拟弹性蛋白多肽的实验数据相似，对于含有(2S,4R)-氟脯氨酸的肽段，II型β -turn结构是稳定的，而对于含有（2S,4S）氟脯氨酸的肽段，相对于典型脯氨酸残基，II型β -turn结构是不稳定的。
Stereoelectronic effects have been identified as contributing factors to the conformational stability of collagen-mimetic peptide sequences. To assess the relevance of these factors within other protein structural contexts, three polypeptide sequences were prepared in which the sequences were derived from the canonical repeat unit (Val-Pro-Gly-Val-Gly) of the protein material elastin. These elastin-mimetic polypeptides, elastin-1, elastin-2, and elastin-3, incorporate (2S)-proline, (2S,4S)-4-fluoroproline, and (2S,4R)-4-fluoroproline, respectively, at the second position of the elastin repeat. Calorimetric and spectroscopic investigations of these three polypeptides indicate that the incorporation of the substituted proline residues had a dramatic effect upon the self-assembly of the corresponding elastin peptide. The presence of (2S,4R)-4-fluoroproline in elastin-3 lowered the temperature of the phase transition and increased the type II beta-turn population with respect to the parent polypeptide, while the presence of (2S,4S)-4-fluoroproline in elastin-2 had the opposite effect. These results suggest that stereoelectronic effects could either enhance or hinder the self-assembly of elastin-mimetic polypeptides, depending on the influence of the proline analogue on the energetics of the beta-turn conformation that develops within the pentapeptide structural repeats above the phase transition. Density functional theory (DFT) was employed to model three possible turn types (beta(I)-,beta(II)-, and inverse gamma-turns) derived from model peptide segments (MeCO-Xaa-Gly-NHMe) (Xaa = Pro, 4S-F-Pro, or 4R-F-Pro) corresponding to the turn-forming residues of the elastin repeat unit (Val-Pro-Gly-Val-Gly). The results of the these calculations suggested a similar outcome to the experimental data for the elastin-mimetic polypeptides, in that type II beta-turn structures were stabilized for peptide segments containing (2S,4R)-fluoroproline and destabilized for segments containing (2S,4S)fluoroproline relative to the canonical proline residue.