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Partitioning of Anesthetics into a Lipid Bilayer and their Interaction with Membrane-Bound Peptide Bundles

Satyavani Vemparala ^*, Leonor Saiz , Roderic G. Eckenhoff  and Michael L. Klein ^*

^* Department of Chemistry and Center for Molecular Modeling, University of Pennsylvania, Philadelphia, Pennsylvania; Integrative Biological Modeling Laboratory, Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York; and Department of Anesthesiology and Critical Care, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania

Correspondence: Address reprint requests to S. Vemparala, Tel.: 215-573-8697; E-mail: vani{at}cmm.upenn.edu.

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-sn-glycero-3-phosphocholine (DOPC) lipids, with embedded -helical peptide bundles based on the membrane-bound portions of the - and -subunits, respectively, of nicotinic acetylcholine receptor. In the molecular dynamics simulations halothane molecules spontaneously partitioned 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 -subunit, an experimentally identified specific binding site. The binding of halothane attenuated the local loop dynamics of -subunit and significantly 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 profile 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.

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