| Abstract
| - Currently, the mechanism by which anesthesia occurs is thought to involve the direct bindingof inhaled anesthetics to ligand-gated ion channels. This hypothesis is being studied using four-α-helixbundles as model systems for the transmembrane domains of the natural “receptor” proteins. This studyconcerns the role in anesthetic binding played by aromatic side chains in the binding cavity of a four-α-helix bundle designed to assume a Rop-like fold. Specifically, the effect of the substitution W15Y onbundle structure, stability, and anesthetic binding energetics was investigated. No appreciable effect ofsubstituting W for Y on the secondary structure or the thermodynamic stability of the four-α-helix bundlewas identified. However, the substitution W15Y resulted in about 6- and 3-fold decreases in halothaneand chloroform binding affinities, respectively. This effect may reflect weaker dipole−aromatic quadrupoleinteractions between the aromatic side chain and the anesthetic in the tyrosine-containing species, whichpossesses the smaller aromatic ring system. For these anesthetic binding proteins, this class of interactionoccurs when the permanent nonspherical distribution of electrons in the aromatic ring systems interactwith the weakly acidic CH group of the anesthetics.
|
