An isothermal titration calorimetry study on the binding of four volatile general anesthetics to the hydrophobic core of a four-alpha-helix bundle protein.
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-alpha-helix bundle (Aalpha(2)-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-alpha-helix bundle, using isothermal titration calorimetry. Isoflurane and sevoflurane both bound to the four-alpha-helix bundle with K(d) values of 140 +/- 10 micro M, whereas enflurane bound with a K(d) value of 240 +/- 10 micro M. The DeltaH degrees 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 DeltaS degrees 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 (Aalpha(2)-L38M)(2) is able to accommodate three modern ether anesthetics with K(d) values that approximate their clinical EC(50) values. The DeltaH degrees 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.
Department of Anesthesia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Tao
T
Zhang
Jonas S
JS
Johansson
D018681:Anesthetics, General / Q000737:chemistry; D018685:Anesthetics, Inhalation / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry / Q000379:methods*; D004735:Energy Transfer; D004737:Enflurane / Q000737:chemistry*; D006221:Halothane / Q000737:chemistry*; D007530:Isoflurane / Q000737:chemistry*; D008738:Methyl Ethers / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D000077149:Sevoflurane; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013696:Temperature; D017186:Titrimetry / Q000379:methods; D014835:Volatilization
D018681:Anesthetics, General; D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D010455:Peptides; D000077149:Sevoflurane; D004737:Enflurane; D007530:Isoflurane; D006221:Halothane