Muralidharan Ajay, Schmidt J R, Yethiraj Arun
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconson 53706, United States.
J Phys Chem B. 2020 Jul 16;124(28):5899-5906. doi: 10.1021/acs.jpcb.0c04312. Epub 2020 Jul 7.
Strategic incorporation of fluorinated prolines can accelerate folding and increase thermal stability of proteins. It has been suggested that this behavior emerges from puckering effects induced by fluorination of the proline ring. We use electronic structure calculations to characterize the potential energy surface (PES) along puckering coordinates for a simple dipeptide model of proline and its fluorinated derivatives. Significant shifts in puckering trends between gas phase and implicit solvent calculations shed light on the effect of solvation on electronic structure and conformational preferences of the ring. This solvation induced puckering effect is previously unknown in the context of prolines. The PES based on implicit solvent is then utilized to construct a correction for a classical force field. The corrected force field accurately captures the experimental conformational equilibrium including the coupling between ring puckering and cis-trans isomerism in fluorinated prolines. This method can be extended to other rings and substituents besides fluorine.
含氟脯氨酸的策略性引入可以加速蛋白质折叠并提高其热稳定性。有人认为这种行为源于脯氨酸环氟化诱导的褶皱效应。我们使用电子结构计算来表征脯氨酸及其氟化衍生物的简单二肽模型沿褶皱坐标的势能面（PES）。气相和隐式溶剂计算之间褶皱趋势的显著变化揭示了溶剂化对环的电子结构和构象偏好的影响。这种溶剂化诱导的褶皱效应在脯氨酸的背景下以前是未知的。然后利用基于隐式溶剂的PES对经典力场进行校正。校正后的力场准确地捕捉了实验构象平衡，包括氟化脯氨酸中环褶皱和顺反异构之间的耦合。这种方法可以扩展到除氟以外的其他环和取代基。
