Kozuch Jacek, Schneider Samuel H, Zheng Chu, Ji Zhe, Bradshaw Richard T, Boxer Steven G
Department of Chemistry, Stanford University, Stanford, California 94305-5012, United States.
Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, U.K.
J Phys Chem B. 2021 May 6;125(17):4415-4427. doi: 10.1021/acs.jpcb.1c00578. Epub 2021 Apr 26.
Noncovalent interactions underlie nearly all molecular processes in the condensed phase from solvation to catalysis. Their quantification within a physically consistent framework remains challenging. Experimental vibrational Stark effect (VSE)-based solvatochromism can be combined with molecular dynamics (MD) simulations to quantify the electrostatic forces in solute-solvent interactions for small rigid molecules and, by extension, when these solutes bind in enzyme active sites. While generalizing this approach toward more complex (bio)molecules, such as the conformationally flexible and charged penicillin G (PenG), we were surprised to observe inconsistencies in MD-based electric fields. Combining synthesis, VSE spectroscopy, and computational methods, we provide an intimate view on the origins of these discrepancies. We observe that the electric fields are correlated to conformation-dependent effects of the flexible PenG side chain, including both the local solvation structure and solute conformational sampling in MD. Additionally, we identified that MD-based electric fields are consistently overestimated in three-point water models in the vicinity of charged groups; this cannot be entirely ameliorated using polarizable force fields (AMOEBA) or advanced water models. This work demonstrates the value of the VSE as a direct method for experiment-guided refinements of MD force fields and establishes a general reductionist approach to calibrating vibrational probes for complex (bio)molecules.
非共价相互作用是凝聚相中从溶剂化到催化的几乎所有分子过程的基础。在物理上一致的框架内对其进行量化仍然具有挑战性。基于实验振动斯塔克效应（VSE）的溶剂致变色可与分子动力学（MD）模拟相结合，以量化小刚性分子中溶质 - 溶剂相互作用的静电力，进而在这些溶质结合到酶活性位点时进行量化。在将这种方法推广到更复杂的（生物）分子，如构象灵活且带电的青霉素G（PenG）时，我们惊讶地发现基于MD的电场存在不一致性。结合合成、VSE光谱和计算方法，我们对这些差异的起源提供了深入的见解。我们观察到电场与柔性PenG侧链的构象依赖性效应相关，包括MD中的局部溶剂化结构和溶质构象采样。此外，我们发现基于MD的电场在带电基团附近的三点水模型中一直被高估；使用可极化力场（AMOEBA）或先进的水模型无法完全改善这一情况。这项工作证明了VSE作为实验指导MD力场优化的直接方法的价值，并建立了一种通用的还原论方法来校准复杂（生物）分子的振动探针。
