Understanding complex mechanisms such as transmembrane ion exchange by proteins in molecular, thermodynamic, and kinetic detail remains a significant challenge. In this talk, I will present an approach to integrate experimental and simulation data to fully characterize Cl–/H+ exchange in ClC antiporters. Rate coefficients are first calculated with reactive and polarizable molecular dynamics simulations and then optimized within a coupled kinetic (Markov state) model to reproduce experimental data. This produces a set of solutions that not only predict new properties but also reveal insight into the series of transitions that define the mechanism, the molecular origin of the unusual 2.2:1 Cl–/H+ stoichiometry, and the influence of protein orientation. I will explain how the consistent exchange ratio is a consequence of kinetic coupling and how the lack of large protein conformational changes suggests a more facile evolutionary connection between chloride channels and more evolved antiporters. Finally, I will discuss how an ensemble of different stochastic exchange pathways, as opposed to a single series of distinct transitions, culminates in the macroscopic observables and thereby helps to explain the underlying molecular mechanism.

Understanding coupled ion exchange in ClC antiporters from the kinetic landscape of Cl-/H+ exchange

2019 Fall National Meeting

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