Collaborative Research: RUI: Mechanism of High Enantiomeric Resolution with Bile Micelles

在这个由化学系化学结构、动力学和机制B计划资助的合作项目中，David Rovnyak、Timothy Strein、Michael Krout和Maria Panteva教授试图了解胆盐组件如何与手性(右手或左手)分子相互作用。天然胆盐因其重要的生理功能和在手性功能材料设计和分析中的潜在应用而受到人们的关注。本项目研究胆汁聚集体复杂表面上的特定区域如何控制与手性客体分子的选择性相互作用。应用磁共振、分离科学、化学合成、热力学和计算方面的先进工具来实现对分子水平相互作用的详细了解。本科生研究人员在整个工作中发挥着主导作用，包括参与实验设计和结果传播。重点是与教员的密切互动，他们在指导学生发展进行独立数据采集和分析所需的专业知识的同时，还会指导学生。这项研究为女性和来自代表不足群体的学生提供了在科学领域规划职业生涯的机会。胆盐经历了依赖浓度的逐步聚集，并伴随着其表面和本体化学的复杂变化。尽管进行了大量研究，但对胆汁聚集体的结构、表面可用的结合部位和对映体选择性的“热点”的精确描述才刚刚开始出现。通过一个扩展的多学科工具包，这项研究提供了对天然和非天然胆盐系统的分子水平相互作用的详细了解。具体地说，这项工作涉及几个互补的焦点：(1)开发更详细的胆汁胶束手性选择模型，包括胆汁脂肪链如何有助于手性选择性增溶客体。本研究采用一维和二维核磁共振实验，以及胶束电动毛细管电泳法(MEKC)，通过测量迁移率差异来表征手性结合。(2)研究了温度变化如何调节手性选择宾客的焓和熵驱动因子。等温滴定量热法用于分离胆汁聚集体与不同对映体结合所产生的热差。(3)通过关键区域的功能化进行胆汁酸类似物的战略合成。这促进了对手性选择机理的理解，并使改进的胆盐类似物的设计成为可能。(4)使用严格的、无偏的分子动力学(MD)模拟自发胆盐组装。在与实验的协同下，计算有助于理解和预测总体结构和稳定性。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

In this collaborative project funded by the Chemical Structure, Dynamics and Mechanisms B Program of the Chemistry Division, Professors David Rovnyak, Timothy Strein, Michael Krout, and Maria Panteva seek to understand how bile salt assemblies interact with chiral (right or left handed) molecules. Naturally occurring bile salts are of interest because of their significant physiological functions and for potential applications in the design and analysis of chiral functional materials. This project investigates how specific regions on the complex surfaces of bile aggregates control selective interactions with chiral guest molecules. Advanced tools in magnetic resonance, separation science, chemical synthesis, thermodynamics and computation are applied to achieve a detailed understanding of molecular-level interactions. Undergraduate researchers take leading roles throughout this work, including participating in experiment design and dissemination of results. Emphasis is on close interactions with faculty, who mentor students while they develop the expertise needed to perform independent data acquisition and analysis. This research provides opportunities for women and for students from under-represented groups who plan careers in science.Bile salts undergo concentration-dependent stepwise aggregation, accompanied by intricate changes in their surface and bulk chemistries. Despite considerable study, a precise description of the structure, the surface-available binding sites, and the enantioselective "hot spots" of bile aggregates is only beginning to emerge. With an expanded, multi-disciplinary toolkit, this research provides detailed understanding of the molecular-level interactions characteristic of both natural and unnatural bile salt systems. Specifically, this work involves several complementary foci: (1) Development of more detailed models for chiral selection by bile micelles, including how bile aliphatic chains contribute to chirally selective solubilization of guests. This research employs a suite of one and two-dimensional NMR experiments, as well as micellar electrokinetic capillary electrophoresis (MEKC), to characterize chiral binding by measurements of mobility difference. (2) Investigation of how temperature changes tune the enthalpic and entropic driving factors for chiral selection of guests. Isothermal titration calorimetry is used to isolate the heat difference associated with binding different enantiomers by bile aggregates. (3) Strategic synthesis of analogues of bile acids through functionalization of key regions. This advances understanding of the mechanisms of chiral selection and permits the design of improved bile salt analogues. (4) Employment of rigorous, unbiased molecular dynamics (MD) simulations of spontaneous bile salt assembly. In synergy with experiments, computations help to understand and predict aggregate structure and stability.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.