Given the challenge of controlling the coupled exchange of ions across a membrane, nature has evolved a number of different effective tools. When the cation involved is the hydrated excess proton, one commonly found rate-limiting factor is the presence or absence of water. In other<br/>words, proteins often use dry regions between protonatable residues to control the rate of proton transport. In this talk, I will present our recently developed multiscale kinetic modeling (MKM) approach which integrates experimental and simulation data to fully characterize the structural, thermodynamic and kinetic landscape of a multistep mechanism and demonstrate its use on the Cl–/H+ exchange process in ClC antiporters. In addition to the wild-type process, I will show how this kind of modeling can be extended to explain mutants and alternative ion flux. These alternative cases highlight even more clearly the regulation of proton flow with hydration. I will present a new method for quantifying hydrogen-bonded water networks, which turns out to be essential to fully characterize coupled hydration and proton transport in these challenging cases. Surprisingly, this definition also describes hydration in the absence of an excess proton quite well, offering a collective variable that can be explicitly sampled to better characterize hydration networks in proteins. I will close by discussing other systems in which hydration plays a central role in the kinetic landscape and competing pathways that collectively enable function.

How proteins use hydration as a kinetic control knob in coupled ion exchange

2019 Fall National Meeting

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