The binding of 10 general anesthetics to a four-alpha-helix bundle protein displays enthalpy-entropy compensation

Isothermal titration calorimetry has been used to characterize the binding of 10 volatile general anesthetics to the hydrophobic core of a four-α-helix bundle protein. This relatively small protein (124 residues) is able to bind a total of 10 volatile general anesthetics with affinities that approximate their respective EC50 values for the anesthetic state, either in man, or in intact animals. This suggests that the four-α-helix bundle represents a good model for the in vivo central nervous system sites of general anesthetic action. The enthalpy changes associated with anesthetic binding to the four-α-helix bundle correlate well with the entropy changes associated with the binding (r = 0.942). Enthalpy-entropy compensation is consistent with the prediction that stronger binding of the anesthetic results in less mobility and therefore greater losses in configurational entropy.