Solvent constraints on the property space of acetylcholine. I. Isotropic solvents

The objective of this study was, first, to examine the property space of a test molecule and, second, to assess solvent constraints. Acetylcholine was chosen as the object of study given its interesting molecular structure and major biological significance. Molecular dynamics simulations of long duration (30 ns) were carried out with acetylcholine in a vacuum or in a box of solvent (chloroform, water, water plus one chloride counterion). For each of the 6000 conformers stored during each run, various geometric and physicochemical properties were calculated, namely, N(+)-C8 distance, solvent-accessible surface area (SAS), polar surface area (PSA), dipole moment, and lipophilicity (virtual log P). The variations of these properties as a function of the dihedral angles tau(2) and tau(3) were unexpectedly broad for such a small molecule. Dipole moment and virtual log P were well correlated, and they varied in a complex manner with the dihedral angles. For example, each of the seven conformational clusters was able to access much of the lipophilicity space of acetylcholine. Solvent constraints on the property space clearly indicate that a polar medium tends to favor polar conformers, whereas the opposite is true for a solvent of low polarity.