Control of Cation Permeation through the Nicotinic Receptor Channel

Open Access
Publisher Website
Google Scholar
Abstract
We used molecular dynamics (MD) simulations to explore the transport of single cations through the channel of the muscle nicotinic acetylcholine receptor (nAChR). Four MD simulations of 16 ns were performed at physiological and hyperpolarized membrane potentials, with and without restraints of the structure, but all without bound agonist. With the structure unrestrained and a potential of −100 mV, one cation traversed the channel during a transient period of channel hydration; at −200 mV, the channel was continuously hydrated and two cations traversed the channel. With the structure restrained, however, cations did not traverse the channel at either membrane potential, even though the channel was continuously hydrated. The overall results show that cation selective transport through the nAChR channel is governed by electrostatic interactions to achieve charge selectivity, but ion translocation relies on channel hydration, facilitated by a trans-membrane field, coupled with dynamic fluctuations of the channel structure. Communication between a cell and its environment relies on channel-forming proteins to provide a low energy pathway for ions to move in and out. Although channel-forming proteins are essential to all life forms, the atomic-scale mechanisms that enable ions to pass through the channel remain elusive due to the lack of experimental approaches to monitor the protein and ion in real time and at atomic resolution. A powerful alternative approach is molecular dynamics (MD) simulation based on the laws of physics applied to the increasing body of protein structures resolved at atomic resolution. Here we present all-atom MD simulations applied to the nicotinic acetylcholine receptor (nAChR) that initiates voluntary movement in skeletal muscle. By focusing on individual permeant cations, we find that selective cation translocation occurs in stages: cations are first selected through a series of oppositely charged residues within the protein vestibule leading to a narrow hydrophobic constriction, but then hydration of the narrow region and dynamic fluctuations of the protein enable the cation to pass through. The findings provide a general framework for understanding how ions are selected for transport based on charge, and how the dynamic interplay between water, the ion, and the channel protein enable rapid ion translocation through the broad class of channel-forming proteins with hydrophobic barriers.