Computational, Experimental and Engineering Foundations of Ionic Channels as Miniaturized Sensors, Devices and Systems

A hierarchical computational strategy combining molecular modeling, electrostatics calculations, molec-ular dynamics, and Brownian dynamics simulations is developed and implemented to compute electrophysiologicallymeasurable properties of the KcsA potassium channel. Models for a series of channels with different pore sizes aredeveloped from the known x-ray structure, using insights into the gating conformational changes as suggested by avariety of published experiments. Information on the pH dependence of the channel gating is incorporated into thecalculation of potential profiles for K ions inside the channel, which are then combined with K ion mobilities inside thechannel, as computed by molecular dynamics simulations, to provide inputs into Brownian dynamics simulations forcomputing ion fluxes. The open model structure has a conductance of 110 pS under symmetric 250 mM K conditions,in reasonable agreement with experiments for the largest conducting substate. The dimensions of this channel areconsistent with electrophysiologically determined size dependence of quaternary ammonium ion blocking from theintracellular end of this channel as well as with direct structural evidence that tetrabutylammonium ions can enter intothe interior cavity of the channel. Realistic values of Ussing flux ratio exponents, distribution of ions within the channel,and shapes of the current-voltage and current-concentration curves are obtained. The Brownian dynamics calculationssuggest passage of ions through the selectivity filter proceeds by a “knock-off” mechanism involving three ions, as hasbeen previously inferred from functional and structural studies of barium ion blocking. These results suggest that thepresent calculations capture the essential nature of K ion permeation in the KcsA channel and provide a proof-of-concept for the integrated microscopic/mesoscopic multitiered approach for predicting ion channel function fromstructure, which can be applied to other channel structures.