Aromatic-proline interactions: electronically tunable CH/π interactions.
Aromatic-proline interactions: electronically tunable CH/π interactions.
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DOI：
10.1021/ar300087y
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发表时间：
2013-04-16
影响因子：
18.3
通讯作者：
Zondlo, Neal J.
中科院分区：
文献类型：
--
作者：
Zondlo, Neal J.
脯氨酸残基在蛋白质折叠、结构和功能中具有独特的作用。脯氨酸与芳香族氨基酸组合构成编码的环状蛋白残基。芳香族蛋白质侧链由其带负电荷的π面限定，而脯氨酸环的面部分带正电荷。这种极性是由于侧链与吸电子蛋白质骨架的两点连接，以及氢的电负性低于碳、氮和氧。与羰基和酰胺氮相邻的氢，Ha和Hδ，分别是最部分正的。脯氨酸的侧链也是构象限制的，允许与芳香族残基相互作用，具有最小的熵或空间罚分。脯氨酸和芳族残基可以有利地相互作用，这是由于疏水效应和π芳族面与极化C-H键之间的相互作用，称为CH/π相互作用。芳香族-脯氨酸相互作用可以局部发生，例如稳定顺式-酰胺键，并且在蛋白质的三级结构中在更大的距离上发生，以及在蛋白质-蛋白质相互作用中在分子间发生。在肽和蛋白质中，芳族脯氨酸序列更容易采用顺式脯氨酰酰胺键，其中芳环与脯氨酸环以顺式构象相互作用。在芳香族脯氨酸序列中，色氨酸和酪氨酸比苯丙氨酸更容易诱导顺式酰胺键，这表明芳香族电子效应。这一结果是CH/π相互作用的预期结果，其中更富电子的芳族化合物将与脯氨酰氢上的部分正电荷具有更强（顺式稳定性更高）的相互作用。在这个帐户中，我们描述了我们的调查本地芳香族脯氨酸相互作用的性质，使用肽模型。我们合成了一系列的26肽，TXPN，不同的X从富电子到贫电子的芳香族氨基酸，并发现人口的顺式-酰胺键（Ktrans/cis）是可调的芳香族电子。与4-取代苯丙氨酸，我们观察到的Hammett芳香族电子和Ktranss/cis之间的相关性，与顺反异构体的电子控制1.0千卡/摩尔。所有芳香族残基表现出更高的顺式人口比丙氨酸或环己基丙氨酸，色氨酸显示出最强的芳香族脯氨酸相互作用。此外，脯氨酸立体电子效应可以调节顺反异构的额外1.0千卡/摩尔。芳香族-脯氨酸相互作用是焓的，与其CH/π相互作用的描述一致。脯氨酸-芳香序列也可以通过芳香环与前面的顺式脯氨酸或顺式脯氨酸之前的Hα的相互作用促进顺式脯氨酰键。在富含脯氨酸的肽中，通常在天然无序蛋白质中发现的序列，由于多种有利的芳香族-脯氨酸相互作用，芳香族残基促进多个顺式酰胺键。总的来说，我们发现芳香族-脯氨酸相互作用在本质上是显著的CH/π，可通过芳香族电子学调节。我们讨论这些数据的背景下，芳香族脯氨酸和芳香族甘氨酸的相互作用，在本地结构，在三级结构中，在蛋白质-蛋白质相互作用，并在蛋白质组装。
Proline residues have unique roles in protein folding, structure, and function. Proline combined with the aromatic amino acids comprise the encoded cyclic protein residues. Aromatic protein side chains are defined by their negatively charged π faces, while the faces of the proline ring are partially positively charged. This polarity results from their two-point connection of the side chain to the electron-withdrawing protein backbone, and the lower electronegativity of hydrogen compared to carbon, nitrogen, and oxygen. The hydrogens adjacent to the carbonyl and amide nitrogen, Ha and Hδ, respectively, are the most partially positive. Proline’s side chain is also conformationally restricted, allowing for interaction with aromatic residues with minimal entropic or steric penalty. Proline and aromatic residues can interact favorably with each other, due to both the hydrophobic effect and the interaction between the π aromatic face and the polarized C-H bonds, called a CH/π interaction. Aromatic-proline interactions can occur locally, for example to stabilize cis-amide bonds, and over larger distances, in the tertiary structures of proteins, and intermolecularly in protein-protein interactions. In peptides and proteins, aromatic-proline sequences more readily adopt cis-prolyl amide bonds, where the aromatic ring interacts with the proline ring in the cis conformation. In aromatic-proline sequences, Trp and Tyr are more likely to induce cis-amide bonds than Phe, suggesting an aromatic electronic effect. This result would be expected for a CH/π interaction, in which a more electron-rich aromatic would have a stronger (more cis-stabilizing) interaction with partial positive charges on prolyl hydrogens. In this Account, we describe our investigations into the nature of local aromatic-proline interactions, using peptide models. We synthesized a series of 26 peptides, TXPN, varying X from electron-rich to electron poor aromatic amino acids, and found that the population of cis-amide bond (Ktrans/cis) is tunable by aromatic electronics. With 4-substituted phenylalanines, we observed a Hammett correlation between aromatic electronics and Ktrans/cis, with cis-trans isomerism electronically controllable by 1.0 kcal/mol. All aromatic residues exhibit a higher cis population than Ala or cyclohexylalanine, with Trp showing the strongest aromatic-proline interaction. In addition, proline stereoelectronic effects can modulate cis-trans isomerism by an additional 1.0 kcal/mol. The aromatic-proline interaction is enthalpic, consistent with its description as a CH/π interaction. Proline-aromatic sequences can also promote cis-prolyl bonds, either through interactions of the aromatic ring with the preceding cis-proline, or with the Hα prior to cis-proline. Within proline-rich peptides, sequences commonly found in natively disordered proteins, aromatic residues promote multiple cis-amide bonds due to multiple favorable aromatic-proline interactions. Collectively, we found aromatic-proline interactions to be significantly CH/π in nature, tunable by aromatic electronics. We discuss these data in the context of aromatic-proline and aromatic-glycine interactions in local structure, in tertiary structure, in protein-protein interactions, and in protein assemblies.
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