Kinetics of Ion Channels by Atomically Detailed Computer Simulations

Cornell University, Ithaca NY

Investigators

Abstract

Computing ion permeation through channels directly from atomically detailed models is far from trivial due to the time scale limitation of the popular Molecular Dynamics approach. The goal of this work is to use an atomically detailed model of the channel to compute its function. A novel computational method, based on a stochastic path formulation, will be used to study the channel kinetics on relevant biological time scales. The new technique extends time scales of simulations by many orders of magnitude. A novel kinetic cycle that provides an easier sampling procedure to compute differences in the weights of trajectories (and relative rates as a function of different voltages, different ions, mutations, etc.) will be employed. Interiors of cells are separated from the rest of the world by membranes that prevent uncontrolled entries and exits of solvated molecules. Channels (protein molecules that are embedded in the membrane) enable selective permeation that is essential for the survival of the cell. The goal of this research is to study ion transport through a channel, using a novel computational technique that was developed recently. This new technique makes it possible to compute atomically detailed trajectories of ion transport at relevant time scales. Computing the experimental observables, with a direct link to biological function, will open new opportunities for synergy of theory and experiment and will further advance quantitative knowledge of structure-function relationship in ion channels. This project is supported by the Molecular Biophysics and Signal Transduction Programs in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Computational Mathematics Program in the Division of Mathematical Sciences in the Mathematical and Physical Sciences Directorate.