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An Isothermal Titration Calorimetry Study on the Binding of Four Volatile General Anesthetics to the Hydrophobic Core of a Four--Helix Bundle Protein

Tao Zhang ^* and Jonas S. Johansson ^*  

Departments of ^*Anesthesia, Biochemistry and Biophysics, and the Johnson Research Foundation, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence: Address reprint requests to Jonas S. Johansson, 319C John Morgan Building, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104 USA. Tel.: 215-349-5472; Fax: 215-349-5078; E-mail: JohanssJ{at}uphs.upenn.edu.

A molecular understanding of volatile anesthetic mechanisms of action will require structural descriptions of anesthetic-protein complexes. Previous work has demonstrated that the halogenated alkane volatile anesthetics halothane and chloroform bind to the hydrophobic core of the four--helix bundle (A₂-L38M)₂ (Johansson et al., 2000, 2003). This study shows that the halogenated ether anesthetics isoflurane, sevoflurane, and enflurane are also bound to the hydrophobic core of the four--helix bundle, using isothermal titration calorimetry. Isoflurane and sevoflurane both bound to the four--helix bundle with K_d values of 140 ± 10 µM, whereas enflurane bound with a K_d value of 240 ± 10 µM. The H° values associated with isoflurane, sevoflurane, and enflurane binding were –7.7 ± 0.1 kcal/mol, -8.2 ± 0.2 kcal/mol, and –7.2 ± 0.1 kcal/mol, respectively. The S° values accompanying isoflurane, sevoflurane, and enflurane binding were -8.5 cal/mol K, -10.4 cal/mol K, and -8.0 cal/mol K, respectively. The results indicate that the hydrophobic core of (A₂-L38M)₂ is able to accommodate three modern ether anesthetics with K_d values that approximate their clinical EC₅₀ values. The H° values point to the importance of polar interactions for volatile general anesthetic binding, and suggest that hydrogen bonding to the ether oxygens may be operative.

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