Conformational changes of proteins lie at the heart of fundamental biological processes. In particular, the opening and closing of voltage-dependent ion channels is modulated by the electric potential difference across the cell membrane. This important example of protein allostery is responsible for the generation of nervous impulses that control muscle movement. How a signal like voltage across a membrane translates to the detailed atomic motions involved in the gating of an ion channel is a remarkable phenomenon. Novel computer simulation methodology is proposed to probe the detailed microscopic mechanisms of voltage-dependent allosteric regulation. Most biomolecular conformational changes occur on timescales which are beyond the ability of current computational methods to simulate. We propose a combination of path-based methods with Markov state models to bridge this timescale gap. Markov models have the potential of overcoming the timescale problem by offering a formalism for extrapolating long time dynamics from the information contained in multiple short simulations. The predictive power and computational efficiency of the resulting Markov model will depend on how faithfully relevant parts of trajectory space are included in the Markov description. Instead of canvassing phase space with a high dimensional grid of order parameters, recently developed methods for finding dynamical paths will be used and extended to help identify important regions. The path-based Markov method will be applied to the conformational changes involved during the gating of the voltage-dependent potassium channels KvAP and Kv1.2. The computational studies will be done in parallel with site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy of these channels prepared in different functional states. The results from simulations will serve initially to guide the experiments, for example, providing suggestions about relevant positions to attach spin labels. The experiments will in turn serve as an important validation of the computational methods. PUBLIC HEALTH RELEVANCE. Voltage-dependent ion channels are life's transistors, responsible for the generation of electrical signals like nervous impulses which control muscle contraction. Their dysfunction leads to a multitude of disorders ranging from multiple sclerosis (MS) to heart disease. Understanding the molecular basis of how these ion channels work can inform the design of novel therapies and drugs to treat these disorders.