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.
Highlights
Channel proteins circumvent the enormous energetic barrier to ion transport imposed by the cell membrane and are essential to all life forms
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
Summary
Channel proteins circumvent the enormous energetic barrier to ion transport imposed by the cell membrane and are essential to all life forms. In simulations containing the entire pore domain in an explicit lipid bilayer, water and ions were excluded from the narrow region of the channel [8]. Manually widening the pore radius by 1.5 Aallowed penetration of both water and ions, giving an ion transport rate approaching that expected from the single channel current amplitude. Neither of these studies included the effect of membrane potential, they concluded that the cryo-electron microscopic structure of the Torpedo nAChR is in the non-conducting, inactive state. Application of a membrane potential promoted water entry, increased the channel radius, and produced ion transport at rates approaching those measured experimentally [10,11,12].
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