Molecular Dynamics of Potassium Channels: Ion Conduction and Activation

Potassium (K⁺) ion channels are molecular machines in cells that catalyze the efficient transport of ions across the cell's low dielectric lipid bilayer. It is well understood that K⁺ ion channels are gated through several mechanisms, such as transmembrane potential, ligands, or mechanical force. In particular, the conserved inverted teepee structure of ion channels and the makings of the ion conducting pathway lend to a belief that structure and function are highly conserved among K⁺ channels. Thus, the approach in molecular dynamics (MD) simulation studies of K⁺ channels is to study simple channels containing conserved components to infer channel properties. Although the field of theoretical and computational models of K⁺ channels is rich, there are details that remain unresolved. For example, the microscopic mechanistic details of how ions cross the ion conduction pathway, as well as the molecular details of the activation mechanism of voltage-gated K⁺ channels are yet to be fully understood. Thus, the work presented in this dissertation details an increased understanding of the multi-ion conduction mechanism of K⁺ channels, revealed from MD simulations of a given force field. We show that small changes, on the order of k_BT, to the key microscopic interactions that occur at the ion conduction pathway affect its occupancy. Then, we show how the occupancy is affected by the details of the force field and importantly the magnitude of the transmembrane potential. Next, we formulate an approach to estimate the K⁺ channel conductance at small physiologically-relevant transmembrane potentials using Green-Kubo linear response theory. Then, we formulate an expanded Markov State Model (MSM) and transition path theory (TPT) framework that addresses the challenges in representing the dynamics of systems with indefinite number of reaction pathways, such as ion channels. Using this expanded MSM/TPT framework, we gain new insight into the mechanistic details of the multi-ion conduction mechanism of K⁺ channels. Lastly, we provide insight into the voltage-dependent activation mechanism of a voltage-activated K⁺ ion channel.