Computational study of the molecular complexes between cholesterol and two isomers of the pralidoxime (PAM)

The key parameters describing a set of association complexes between cholesterol and each of the Z and E isomers of the pralidoxime cation (2-PAM) are discussed in a comparative study based on HF, MP2, and B3LYP calculations. The aim of the investigation was to probe the potential role of cholesterol to assist in the cell membrane translocation of the very polar 2-PAM, an efficient antidote against organophosphate intoxication. A series of three cholesterol-2-PAM association complexes are found for each 2-PAM geometric isomer. Optimized geometries, energy data, charge distribution and natural bond orbital are thoroughly analyzed for each of them. These results predict the formation of one complex resulting from ion-dipole interactions and of two others in which (PAM) = N-OH... OH- (from cholesterol) hydrogen bonds are the dominant interactions. Stabilization energies range between 10 and 20 kcal mol(-1) for all of these complexes. These values support the hypothesis of diffusion of a stable association of 2-PAM with cholesterol as a mechanism of transport across a biological membrane. (D 2007 Elsevier B.V. All rights reserved.