Applied field nonequilibrium molecular dynamics simulations of ion exit from a $beta;-barrel model of the L-type calcium channel

Abstract

We present results of applied field nonequilibrium molecular dynamics simulations (AF NEMD) of a minimal β-barrel model channel intended to represent an L-type calcium channel that suggests a possible relationship between glutamate side chain conformational changes and ion flux in calcium channels. The β-barrel is used to provide a scaffolding for glutamate side chains and a confinement for electrolyte of dimensions similar to the expected channel structure. It was preloaded with ions to explore relative rates of ion exit for different occupancy configurations. Our simulations with an asymmetrical flexible selectivity filter represented by four glutamate side chains (EEEE), one of which differs in initial dihedrals from the other three, indicate a plausible mechanism for the observed anomalous mole fraction effect seen in calcium channels. Apparent rates of electric field-induced exit from channels preloaded with three Na + ions are much higher than for channels with one Ca 2+ followed by two Na + ions, consistent with the common notion that Ca 2+ block of Na + current is due to competition between the Ca 2+ and Na + ions for the negatively charged (EEEE) locus. In our model, the Ca 2+ ion ligates simultaneously to the four negatively charged glutamate side chains and sterically blocks the permeation pathway. Ca 2+ -relief of Ca 2+ -block is suggested by a much higher rate of exit for channels preloaded with three Ca 2+ ions than for channels with two Ca 2+ ions.