This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Proposal Keywords molecular dynamics simulations anesthetic effects ion channels Abstract: The quest for a molecular understanding of the mechanisms of low-affinity neuronal drugs, particularly general anesthetics and alcohols, remains a clinical and scientific challenge. Because multiple lines of experimental evidence indicate that anesthetics affect protein functions without drastically changing the protein structures, it is highly likely that these low-affinity drugs exert their action by altering protein dynamics. The proposed research seeks to delineate molecular dynamical events that are of physiological importance. In this application, we propose to investigate the anesthetic effects on transmembrane ion channel dynamics in a fully hydrated membrane system using large-scale molecular dynamics (MD) simulations. Two model ion channels with different scales of complexity will be used to elucidate dynamical properties that are of functional significance. The first model will be a gramicidin A (gA) channel, the structure of which has been experimentally solved to the atomic resolution. This channel is included to compare the simulation results with our experimental data. The second channel will be a pentameric complex (2alpha4/3beta2) made of the transmembrane domains of the alpha4 and beta2 subunit of human neuronal acetylcholine receptors (nAChR). The subtype 2alpha4/3beta2 receptor of neuronal nAChR is predominantly distributed in brain and is functionally sensitive to general anesthetics and alcohols. An atomic model of muscle nAChR from Torpedo electric ray has been provided recently by electron microscopy. The structure of the muscle nAChR will be used as a template for the structure homology modeling of the 2alpha4/3beta2 receptor of nAChR, considering that the sequence identity of 2alpha4/3beta2 to the muscle type is as high as 60%. Molecular dynamics simulations of neuronal nAChR 2alpha4/3beta2 subtype, even with short simulation time, will provide much useful information for understanding the underlying molecular mechanisms of anesthetic actions on this type of ligand-gated ion channels. The central hypothesis is that the action of low-affinity drugs on transmembrane ion channels cannot in many cases be described by the conventional lock-and-key concept of protein-drug interaction. Instead, a tertiary structural consequence caused by dynamic changes at the channel-membrane-water interface is of functional importance.
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