inactivation process in WT channels. To investigate the structural changes that underlie the unusual behaviour of this mutant, we performed a series of MD simulations of the pore domain of WT hKv1.5 and T480A. Analysis of the trajectories shows that T480A affects the stability and flexibility of the filter region and the surrounding pore loop. These results show that residue T480 (located outside the pore region that determines the integrity of the selectivity filter) affects the stability of

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... e filter and influences C-type inactivation. The potassium ion channel, KcsA, gates the passage of ions through cell membranes in response to a change in pH. Recent experimental results have demonstrated the existence of two gates in KcsA: an intracellular gate and a gate at the selectivity filter. Lowering the pH opens the intracellular gate allowing ions to pass. After a period of time, however, the channel inactivates by constricting the selectivity filter and impeding the flow of ions even though the bottom gate remains open. We have used path-based molecular dynamics simulations to probe the detailed mechanism of this phenomenon by finding dynamical pathways to inactivation in KcsA. We have computed free energies and rates of inactivation that agree with recent experimental results. We also provide a molecular rationalization for the coupling between the opening and closing of the lower gate and the inactivation of the selectivity filter.