Molecular insight into ion-driven processes requires a precise knowledge of how the energetics, structures, dynamics of ions differ between hydrated and biomolecule-bound states. While first principles quantum mechanical models can yield reliable estimates for relative binding energies, estimates for thermodynamics and ion-binding response are subject to limitations from conformational sampling and system size. In contrast, molecular mechanics models that do not describe many body effects explicitly can technically get past sampling/system-size issues, but suffer severely from accuracy. Polarizable models are being developed as a compromise between accuracy and efficiency, but are they sufficiently reliable to derive causalities? In general, where do we stand in terms of being able to use molecular simulations to understand selective ion binding to biomolecules, and the response of ion binding to biomolecular function? Here I’ll discuss these issues and potential solutions in the context of our work on potassium channels that excel at transporting K+ ions across cell membranes, while at the same time discriminating K+ from the slightly smaller Na+ ions.
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