J Phys Chem B. 2019 Jan 10;123(1):138-147. doi: 10.1021/acs.jpcb.8b10864. Epub 2018 Dec 26.
Cis-trans isomerization of proline is involved in various biological processes, such as protein folding, cell signaling, and ion-channel gating. Polyproline is a useful system for better understanding proline isomerization because it exists predominantly as two forms, all-cis polyproline I (PPI) and all-trans polyproline II (PPII) helices. The stability of PPI and PPII can be modulated by various effects, including aromatic-proline interactions, terminal charges, and stereoelectronic effects. Here, we used a series of oligoproline peptides in which positively charged or negatively charged amino acids were incorporated into the termini to investigate their effects on polyproline conformation. Circular dichroism measurements show that a cationic residue at the C-terminus or an anionic residue at the N-terminus increases the stability of a PPII helix; in particular, the C-terminal cationic residues impose an enormous impact on PPII stability. The electrostatic attractions between a cationic sidechain and the C-terminal carboxylate exhibit a greater effect than those between an anionic sidechain and the N-terminal ammonium on the conversion of PPII to PPI, suggesting that the stabilization effect of electrostatic interactions on PPII is directional. In contrast, incorporating a cationic residue seems more favorable than adding an anionic residue into the N-terminus because the cationic residue can stabilize PPI. Moreover, the predicted dipole moments from optimized oligopeptide models reveal that the macrodipole of the peptides with a cationic residue at the C-terminus exhibits the opposite direction to that of other peptides in the PPI conformation, suggesting that such a dipole distortion may cause these peptides to disfavor PPI helices. Together, we have found that the introduction of terminal electrostatic interactions can have a significant effect on PPII stability, providing useful information to the design of polyproline-based scaffolds for biomedical applications.
脯氨酸的顺反异构化参与了各种生物过程，如蛋白质折叠、细胞信号转导和离子通道门控。聚脯氨酸是更好地理解脯氨酸异构化的有用体系，因为它主要存在两种形式，全顺式聚脯氨酸 I（PPI）和全反式聚脯氨酸 II（PPII）螺旋。PPI 和 PPII 的稳定性可以通过各种效应进行调节，包括芳香族-脯氨酸相互作用、末端电荷和立体电子效应。在这里，我们使用了一系列寡聚脯氨酸肽，其中在末端掺入带正电荷或带负电荷的氨基酸，以研究它们对聚脯氨酸构象的影响。圆二色性测量表明，C 末端带正电荷的残基或 N 末端带负电荷的残基会增加 PPII 螺旋的稳定性；特别是，C 末端带正电荷的残基对 PPII 的稳定性有巨大影响。阳离子侧链与 C 末端羧基之间的静电吸引比对阴离子侧链与 N 末端铵之间的静电吸引对 PPII 向 PPI 的转化影响更大，这表明静电相互作用对 PPII 的稳定作用具有方向性。相比之下，在 N 末端掺入带正电荷的残基似乎比加入带负电荷的残基更有利，因为带正电荷的残基可以稳定 PPI。此外，优化寡肽模型的预测偶极矩表明，C 末端带正电荷的肽的宏观偶极矩在 PPI 构象中与其他肽的方向相反，这表明这种偶极矩扭曲可能使这些肽不利于 PPI 螺旋。总之，我们发现引入末端静电相互作用对 PPII 的稳定性有显著影响，为基于聚脯氨酸的生物医学应用支架的设计提供了有用的信息。
