London Dispersion Interactions in Molecular Recognition by Acetylcholinesterase

Abstract

Interaction of the aromatic residues W84, Y130 and F330 (or Y330) of Torpedo californica (Nair et al., 1994) and mouse AChEs with the quaternary ammonium function of ligands and substrates has been probed by quantitative structure-activity relationship (QSAR) and site-directed mutagenesis studies. For a series of ten meta-substituted aryl trifluoroketone inhibitors, m-XC6H4COCF3 (X = H, Me, CF3, Et, iPr, tBu, NO2, NH2, NMe2, Me3N+), inhibitor potency (i. e. pKi) is not correlated with substituent hydrophobicity, but is well described by a three-dimensional correlation with the molar refractivity (MR) and σw of the substituents. MR depends on surface area and polarizability, and thus is a measure of London dispersion and other induced polarization interactions between ligands and the aromatic residues of the quaternary ammonium binding locus of the active site. Of the 107-fold range of inhibitor potency, 105 arises from the MR sensitivity, and the corresponding linear subcorrelation indicates that all substituents share a common binding locus and interaction mechanism. A reasonable linear correlation of pKi for inhibition by the m-Me3N+ ketone versus amino acid MR values for a series of W84 mutants of mouse AChE, which includes W84Y, W84F and W84A, indicates that about a third of the binding free energy in the quaternary ammonium binding locus comes from interaction with the tryptophan indole ring. For the native mouse enzyme and these three mutants, a plot of pKi for inhibition by the m-Me3C ketone versus pKi for inhibition by the m-Me3N+ ketone is linear with a slope of 0.7. The greater sensitivity of the charged inhibitor indicates that additional interactions, not enjoyed by the neutral inhibitor, with W84 are operating. These likely include ion-quad-rupole and ion-polarizability interactions with the it-electrons of W84 (Kim et al., 1994). Similar correlations for substrate turnover support the importance of dispersion interactions in AChE catalysis. These studies indicate that the aromatic residues in the quaternary ammonium binding locus of the active site do not function as classical anionic sites.