Entropy-driven interactions of anesthetics with membrane proteins.
Thermodynamic analysis of anesthetic effects on Ca2+-ATPase activity was performed to evaluate the feasibility of anesthetic binding and gain insight into the molecular events underlying the anesthetic-enzyme interactions. The Ca2+-ATPases, integral membrane proteins vital in cellular Ca2+ regulation, are suitable models for investigation of the mechanism of anesthetic action on membrane proteins that are targeted by the anesthetics. Ca2+-ATPase of plasma membrane, PMCA, and SERCA1 in the intracellular sarcoplasmic reticulum membrane were used to study two general anesthetics: halothane, a halogenated two-carbon alkane; and propofol, an intravenous, strongly lipophilic-substituted phenol. Interactions of both anesthetics result in a negative Gibbs free energy change, which in both enzymes is more favorable for the more lipophilic propofol than halothane. Temperature dependence (more negative change in Gibbs free energy at increased temperature) is in agreement with predominantly nonpolar interactions. The interactions are entropy-driven, characterized by positive enthalpy which is overcompensated by positive entropy changes. This is in contrast to the reported in literature enthalpy-driven anesthetic binding to soluble proteins. The possible contributions to the observed positive entropy change are discussed including displacement of ordered water molecules by anesthetic binding in nonpolar cavities in the membrane proteins and subtle structural rearrangements.
Lopez
M M
MM
Department of Anesthesiology/CCM, The Johns Hopkins University, Baltimore, Maryland 21287, USA.
Kosk-Kosicka
D
D
D000777:Anesthetics / Q000378:metabolism*; D001665:Binding Sites; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D019277:Entropy; D006221:Halothane / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism*; D008956:Models, Chemical; D015742:Propofol / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D012996:Solutions; D013816:Thermodynamics
D000777:Anesthetics; D008565:Membrane Proteins; D012996:Solutions; D000252:Calcium-Transporting ATPases; D006221:Halothane; D015742:Propofol