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A Model Membrane Protein for Binding Volatile Anesthetics

Shixin Ye ^*, Joseph Strzalka ^*, Inna Y. Churbanova ^*, Songyan Zheng , Jonas S. Johansson  and J. Kent Blasie ^*

^* Department of Chemistry, Department of Anesthesiology, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence: Address reprint requests to J. Kent Blasie, E-mail: jkblasie{at}sas.upenn.edu.

Earlier work demonstrated that a water-soluble four-helix bundle protein designed with a cavity in its nonpolar core is capable of binding the volatile anesthetic halothane with near-physiological affinity (0.7 mM K_d). To create a more relevant, model membrane protein receptor for studying the physicochemical specificity of anesthetic binding, we have synthesized a new protein that builds on the anesthetic-binding, hydrophilic four-helix bundle and incorporates a hydrophobic domain capable of ion-channel activity, resulting in an amphiphilic four-helix bundle that forms stable monolayers at the air/water interface. The affinity of the cavity within the core of the bundle for volatile anesthetic binding is decreased by a factor of 4–3.1 mM K_d as compared to its water-soluble counterpart. Nevertheless, the absence of the cavity within the otherwise identical amphiphilic peptide significantly decreases its affinity for halothane similar to its water-soluble counterpart. Specular x-ray reflectivity shows that the amphiphilic protein orients vectorially in Langmuir monolayers at higher surface pressure with its long axis perpendicular to the interface, and that it possesses a length consistent with its design. This provides a successful starting template for probing the nature of the anesthetic-peptide interaction, as well as a potential model system in structure/function correlation for understanding the anesthetic binding mechanism.

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				I. Y. Churbanova, A. Tronin, J. Strzalka, T. Gog, I. Kuzmenko, J. S. Johansson, and J. K. Blasie Monolayers of a Model Anesthetic-Binding Membrane Protein: Formation, Characterization, and Halothane-Binding Affinity Biophys. J., May 1, 2006; 90(9): 3255 - 3266. [Abstract] [Full Text] [PDF]