2815 - Biophysical Journal Volume 91 October 2006 28152825...

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Partitioning of Anesthetics into a Lipid Bilayer and their Interaction with Membrane-Bound Peptide Bundles Satyavani Vemparala,* Leonor Saiz, y Roderic G. Eckenhoff, z and Michael L. Klein* *Department of Chemistry and Center for Molecular Modeling, University of Pennsylvania, Philadelphia, Pennsylvania; y Integrative Biological Modeling Laboratory, Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York; and z Department of Anesthesiology and Critical Care, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania ABSTRACT Molecular dynamics simulations have been performed to investigate the partitioning of the volatile anesthetic halothane from an aqueous phase into a coexisting hydrated bilayer, composed of 1,2-dioleoyl-s n -glycero-3-phosphocholine (DOPC) lipids, with embedded a -helical peptide bundles based on the membrane-bound portions of the a - and d -subunits, respectively, of nicotinic acetylcholine receptor. In the molecular dynamics simulations halothane molecules spontaneously par- titioned into the DOPC bilayer and then preferentially occupied regions close to lipid headgroups. A single halothane molecule was observed to bind to tyrosine (Tyr-277) residue in the a -subunit, an experimentally identiFed speciFc binding site. The binding of halothane attenuated the local loop dynamics of a -subunit and signiFcantly influenced global concerted motions suggesting anesthetic action in modulating protein function. Steered molecular dynamics calculations on a single halothane molecule partitioned into a DOPC lipid bilayer were performed to probe the free energy proFle of halothane across the lipid- water interface and rationalize the observed spontaneous partitioning. Partitioned halothane molecules affect the hydrocarbon chains of the DOPC lipid, by lowering of the hydrocarbon tilt angles. The anesthetic molecules also caused a decrease in the number of peptide-lipid contacts. The observed local and global effects of anesthetic binding on protein motions demonstrated in this study may underlie the mechanism of action of anesthetics at a molecular level. INTRODUCTION Despite the use of general anesthetics (GA) in medicine for more than 150 years, their mechanism of action on the central nervous system remains a matter of debate. Two contenders for the primary site of action in this controversy are the lipid membrane and the proteins embedded in it. Starting with the early experiments by Meyer and Overton (1,2), many studies (3,4) have suggested that the lipid bilayers act as primary targets for anesthetics, because of their hydrophobicity. The GA molecules achieve a high concentration in the lipid bilayer, and were suggested to perturb its structure and dynamics, only indirectly affecting membrane protein function through nonspeciFc mechanisms. On the other hand, proteins have hydrophobic domains, which make them equally plausible targets, as demonstrated in the case of Fre±y luciferase (5) or apoferritin (6). ²urther support for protein-centered hypoth-
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This note was uploaded on 12/13/2010 for the course GENETIK 12 taught by Professor Atillabasar during the Spring '10 term at Istanbul Technical University.

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2815 - Biophysical Journal Volume 91 October 2006 28152825...

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