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ANESTHETIC PHARMACOLOGY

The Common Chemical Motifs Within Anesthetic Binding Sites

Edward J. Bertaccini, MD^*, James R. Trudell, PhD^*, and Nicholas P. Franks, PhD

From the *Department of Anesthesia, Stanford University School of Medicine, Stanford, California; Department of Veterans Affairs, Palo Alto VA Health Care System, Palo Alto, California; and Biophysics Section, Blackett Laboratory, Imperial College, London, SW7 2AZ, UK.

Address correspondence and reprint requests to Edward J. Bertaccini, MD, Department of Anesthesia, 112A Palo Alto VA Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304. Address e-mail to edwardb{at}stanford.edu.

BACKGROUND: It is not yet possible to obtain crystal structures of anesthetic molecules bound to proteins that are plausible neuronal targets; for example, ligand-gated ion channels. However, there are x-ray crystal structures in which anesthetics are complexed with proteins that are not directly related to anesthetic action. Much useful information about anesthetic–protein interactions can be derived from the x-ray crystal structures of halothane–cholesterol oxidase, bromoform–luciferase, halothane–albumin, and dichloroethane–dehalogenase. These structures show anesthetic-protein interactions at the atomic level.

METHODS: We obtained the known coordinate files for bromoform–luciferase, halothane– albumin, dichloroethane–dehalogenase, and halothane–cholesterol oxidase. These were then modified by adding hydrogens, edited into subsets, and underwent a series of restrained molecular mechanics optimizations. Final analysis of anesthetic polarization within the anesthetic binding site occurred via combined molecular mechanics–quantum mechanics calculations.

RESULTS: The anesthetic binding sites within these well-characterized anesthetic– protein complexes possess a set of common characteristics that we refer to as "binding motifs." The common features of these motifs are polar and nonpolar interactions within an amphiphilic binding cavity, including the presence of weak hydrogen bond interactions with amino acids and water molecules. Calculations also demonstrated the polarizing effect of the amphipathic binding sites on what are otherwise considered quite hydrophobic anesthetics. This polarization appears energetically favorable.

CONCLUSIONS: Anesthetic binding to proteins involves amphipathic interactions.

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