Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
Phys Chem Chem Phys. 2022 Jun 8;24(22):13571-13586. doi: 10.1039/d2cp00857b.
n→π* interactions between consecutive carbonyls stabilize the α-helix and polyproline II helix (PPII) conformations in proteins. n→π* interactions have been suggested to provide significant conformational biases to the disordered states of proteins. To understand the roles of solvation on the strength of n→π* interactions, computational investigations were conducted on a model n→π* interaction, the twisted-parallel-offset formaldehyde dimer, as a function of explicit solvation of the donor and acceptor carbonyls, using water and HF. In addition, the effects of urea, thiourea, guanidinium, and monovalent cations on n→π* interaction strength were examined. Solvation of the acceptor carbonyl significantly strengthens the n→π* interaction, while solvation of the donor carbonyl only modestly weakens the n→π* interaction. The n→π* interaction strength was maximized with two solvent molecules on the acceptor carbonyl. Urea stabilized the n→π* interaction simultaneous engagement of both oxygen lone pairs on the acceptor carbonyl. Solvent effects were further investigated in the model peptides Ac-Pro-NMe, Ac-Ala-NMe, and Ac-Pro-NMe. Solvent effects in peptides were similar to those in the formaldehyde dimer, with solvation of the acceptor carbonyl increasing n→π* interaction strength and resulting in more compact conformations, in both the proline and ring puckers, as well as a reduction in the energy difference between these ring puckers. Carbonyl solvation leads to an energetic preference for PPII over both the α-helix and β/extended conformations, consistent with experimental data that protic solvents and protein denaturants both promote PPII. Solvation of the acceptor carbonyl weakens the intraresidue C5 hydrogen bond that stabilizes the β conformation.
羰基之间的 n→π* 相互作用稳定了蛋白质中的α-螺旋和聚脯氨酸 II 螺旋（PPII）构象。n→π* 相互作用被认为为蛋白质的无规卷曲状态提供了显著的构象偏向。为了了解溶剂对 n→π* 相互作用强度的影响，我们对模型 n→π* 相互作用——扭曲平行偏移甲醛二聚体，进行了计算研究，考察了供体和受体羰基的显式溶剂化对 n→π* 相互作用的影响，使用的溶剂有水和 HF。此外，还研究了脲、硫脲、胍和单价阳离子对 n→π* 相互作用强度的影响。受体羰基的溶剂化显著增强了 n→π* 相互作用，而供体羰基的溶剂化仅适度削弱了 n→π* 相互作用。受体羰基上有两个溶剂分子时，n→π* 相互作用强度最大。脲稳定了 n→π* 相互作用，同时使受体羰基上的两个氧孤对参与其中。我们进一步在模型肽 Ac-Pro-NMe、Ac-Ala-NMe 和 Ac-Pro-NMe 中研究了溶剂效应。在肽中的溶剂效应与甲醛二聚体中的相似，受体羰基的溶剂化增加了 n→π* 相互作用强度，并导致更紧凑的构象，在脯氨酸和环褶皱中都是如此，同时也降低了这些环褶皱之间的能量差。羰基的溶剂化导致对 PPII 的能量偏好，超过了α-螺旋和β/扩展构象，这与实验数据一致，即质子溶剂和蛋白质变性剂都促进 PPII。受体羰基的溶剂化削弱了稳定β构象的 C5 内残基氢键。
