Ion channels are highly specific membrane-scanning protein structures which facilitate and control the passage of ions across the cell membrane, our goal is to gain deeper insight into the structure and function of some important ion channels and lay the foundations for an understanding of the fundamental microscopic principles governing ion permeation using computational methods. We will study several aspects of the KcsA channel, the only channel selective for potassium ions for which the three-dimensional (3d) structure was determined at atomic resolution. In addition, we will construct and refine 3d models of important K-channels. Using their homology t9 the known KcsA , and generate models of inhibiting toxins associated with the channel models using data from mutant cycles. These modeling projects are inter-related, e.g., the toxin/channel complexes are helpful for validating the channel models. Lastly, we will establish the range of microscopic validity of descriptions of ion permeation (Brownian dynamics, Nernst-Planck, Poisson-Nernst-Planck, Poisson- Boltzmann, and kinetic rate models) in relation to molecular dynamics stimulations and elucidate the importance of electrostatics on the charge specificity of porins. New software for simulating ion permeation will be developed and freely distributed for research and education. Our goal with these computations is to complement the (sometimes limited) information that is currently available from experiments and, ultimately, progress in our understanding of ion channels. In addition, the calculations are used to characterize various microscopic factors which cannot easily be accessed experimentally, but are essential for understanding the molecular determinants of channel function.
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