Ion channels are membrane proteins that allow a rapid cellular response to external stimuli by facilitating ionic fluxes across membranes. The single channel current-voltage (I-V) relationship is crucial for understanding the biophysical properties of specific channels, and these measurements are routine using standard electrophysiological techniques. To date, atomistic simulations have been much less successful at reproducing I-V relationships due to the slow timescale of ion permeation, but limited success has been made using brute force simulation on special purpose hardware. Here, we explore the use of the Weighted Ensemble (WE) method to efficiently simulate ion permeation using fully-atomistic models. WE is a type of transition path sampling that focuses computational resources on rare transition state configurations important in the reaction scheme. WE sampling carries out many independent simulations, each with a statistical weight, and tracks these simulations through the reaction space. Simulations in underrepresented regions are split to increase sampling, and in overrepresented regions are merged to reduce the computational burden in well sampled areas. Eventually, the method convergences on an ensemble of trajectories describing ion permeation, which are weighted according to their correct probabilities. Because WE can capture rare events efficiently, we have already shown that it can dramatically increase the efficiency of computing I-V relationships for a ion channel model. Here, we describe our work applying this methodology to the biological K+ channel KcsA in an attempt to map out its I-V relationship at physiological voltages.

In silico measurements of the ionic current in a K+ ion channel using weighted ensemble simulations

253rd National Meeting (2017)

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