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

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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.