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Biophys. J. BioFAST: First Published July 28, 2006. doi:10.1529/biophysj.106.085324
© 2006 by the Biophysical Society.

A more recent version of this article appeared on October 15, 2006.
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Satyavani Vemparala
Michael L Klein
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BIOPHYSICAL THEORY AND MODELING

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

Satyavani Vemparala 1*, Leonor Saiz 2, Roderic G Eckenhoff 1 and Michael L Klein 1

1 University of Pennsylvania
2 Memorial Sloan Kettering Cancer Center

* To whom correspondence should be addressed. E-mail: vani{at}cmm.upenn.edu.

Submitted on March 17, 2006
Revised on May 3, 2006
Accepted on 28 June 2006


  Abstract
Molecular dynamics (MD) 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 {alpha}-helical peptide bundles based on the membrane-bound portions of the {alpha}- and {delta}-subunits, respectively of nicotinic acetylcholine receptor (nAChR). In the MD simulations halothane molecules spontaneously partitioned into the DOPC bilayer and then preferentially occupied regions close to lipid head groups. A single halothane molecule was observed to bind to tyrosine (TYR 277) residue in the {alpha}-subunit, an experimentally identified specific binding site. The binding of halothane attenuated the local loop dynamics of {alpha}-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 molecular level.

Key Words: Molecular dynamics simulation, anesthetic mechanism, halothane, nicotinic acetylcholine receptor, steered molecular dynamics




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Copyright © 2006 by the Biophysical Society.