Volatile anesthetic modulation of oligomerization equilibria in a hexameric model peptide

Edited by Takashi Gojobori

Received 4 October 2004; received in revised form 29 October 2004; accepted 31 October 2004. published online 17 November 2004.

Abstract

To determine if occupancy of interfacial pockets in oligomeric proteins by volatile anesthetic molecules can allosterically regulate oligomerization equilibria, variants of a three-helix bundle peptide able to form higher oligomers were studied with analytical ultracentrifugation, hydrogen exchange and modeling. Halothane shifted the oligomerization equilibria towards the oligomer only in a mutation predicted to create sufficient volume in the hexameric pocket. Other mutations at this residue, predicted to create a too small or too polar pocket, were unaffected by halothane. Inhaled anesthetic modulation of oligomerization interactions is a novel and potentially generalizable biophysical basis for some anesthetic actions.

Keywords: Halothane, Protein cavities, Anesthesia, Hydrogen exchange, Analytical ultracentrifugation

a Departments of Biophysics and Biochemistry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

b Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, USA

c Department of Anesthesia, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6112, USA

d Departments of Biophysics, Biochemistry, and the Johnson Research Foundation, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

Corresponding author. Fax: +1 215 349 5078

PII: S0014-5793(04)01355-9

doi:10.1016/j.febslet.2004.10.087

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