Interactions of Anesthetics with the Water-Hexane Interface
A Molecular Dynamics Study
Christophe Chipot
, Michael A. Wilson
and Andrew Pohorille
Planetary
Biology Branch
NASA -- Ames Research Center
MS 239-4
Moffett Field, California 94035-1000
Department
of Pharmaceutical Chemistry,
University of California, San Francisco,
San Francisco, California 94143
on leave
from:
Laboratoire de Chimie Théorique,
Unité de Recherche Associée au CNRS n
510,
Université Henri Poincaré-Nancy I, BP. 239,
54506 Vand
uvre-lès-Nancy
Cedex -- France
Abstract
The free energy profiles characterizing the transfer of nine solutes across the
liquid-vapor interfaces of water and hexane, and across the water-hexane interface were
calculated from molecular dynamics simulations. Among the solutes were n-butane and three
of its halogenated derivatives, as well as three halogenated cyclobutanes. The two
remaining molecules, dichlorodifluoromethane and 1,2-dichloroperfluoroethane, belong to
series of halo-substituted methanes and ethanes, described in previous studies (J.
Chem. Phys., 1996, 104, 3760). Each series of molecules contains
structurally similar compounds that greatly differ in anesthetic potency. The accuracy of
the simulations was tested by comparing the calculated and the experimental free energies
of solvation of all nine compounds in water and in hexane. In addition, the calculated and
the measured surface excess concentration of n-butane at the water liquid-vapor interface
were compared. In all cases, good agreement with experimental results was found. At the
water-hexane interface, the free energy profiles for polar molecules exhibited significant
interfacial minima, whereas the profiles for nonpolar molecules did not. The existence of
these minima was interpreted in terms of a balance between the free energy contribution
arising from solute-solvent interactions and the work to form a cavity that accomodates
the solute. These two contributions change monotonically, but oppositely across the
interface. The interfacial solubilities of the solutes, obtained from the free energy
profiles, correlate very well with their anesthetic potencies. This is the case even when
the Meyer-Overton hypothesis, that predicts a correlation between anesthetic potency and
solubility in oil, fails. These results suggest that an interface between polar and
nonpolar environments, such as the surface of the neuronal membrane, or a water-exposed
portion of a protein receptor, is a more likely site of anesthetic action than the
interior of the membrane.
