Molecular Modeling of Charge Selectivity in Pentameric Ligand-Gated Ion Channels

Abstract

One of the most unique properties of pentameric ligand-gated ion channels (pLGICs) is that the superfamily contains both anion- and cation-selective members; understanding the relationship between the primary sequence and charge selectivity in these channels has been an active field for many years. This concept has historically been explored electrophysiologically owing to the lack of structural models, but recent advances in X-ray crystallography and cryo-electron microscopy have provided the field with several structures. We now have structural models for both anion- and cation-selective pLGICs. Therefore, it seems pertinent to perform computational simulations on these various structures in order to elucidate the molecular basis by which charge selectivity in these channels is achieved, and to understand how mutations that alter this selectivity perturb the ion-permeation free-energy landscape. Although electrophysiological studies of charge selectivity are often limited to the estimation of reversal potentials under dilution conditions, computational simulations provide a broad array of techniques to tackle this issue. Using both molecular dynamics and Brownian dynamics (BD), we calculated potential-of-mean-force profiles along the permeation axis. Using BD, we also calculated reversal potentials under dilution conditions, which are directly comparable to those obtained experimentally. Also using BD, we calculated the fraction of the current carried by either cations or anions under symmetric-salt conditions. We compared these different methods for computing the selectivity of multiple pLGICs both among different computational methods and with experiments. Our simulations recapitulate the notion that charge selectivity does not necessarily arise from charged side chains, suggest that the barrier to anions presented by cation-selective pLGICs and the barrier to cations presented by anion-selective pLGICs are located in different regions of the pore, and show that some open-channel structural models do not display, in simulations, the selectivity observed in experiments.