Conformational population distribution of acetylcholine, nicotine and muscarine in vacuum and solution

This work presents a theoretical, unified, study of the conformational distribution of acetylcholine, nicotine and muscarine in vacuum and aqueous solution at physiological temperature. The energetic and geometric data are obtained at the MP2/cc-pVDZ level, whereas the solvent effect is described by means of the PCM continuum model. The population of conformers is derived from a conformational partition function, including the effects of the rotovibrational coupling and the conformational kinetic energy. For muscarine we find, in vacuum and solution, only one significantly populated conformer. In this conformer, muscarine exhibits a gauche conformation. For nicotine, only two conformations are found, similarly populated in vacuum. In solution only one of these conformations remains, corresponding to an almost perpendicular orientation of the pyrrolidine and pyridine rings. On the other hand, acetylcholine in vacuum and solution accumulates its population in a zone where the cationic head is in a gauche conformation. This conformational zone is defined by the orientation of the acetoxy moiety. For the three molecules, the most populated conformers in solution are compared using internuclear distances. The results show that the conformers of acetylcholine and nicotine exhibit a similar pharmacophoric distribution (using the oxygen of the acetylcholine ester group). In addition, this acetylcholine conformer also exhibits a similar pharmacophoric pattern to the conformer of muscarine (using the acetylcholine carbonyl oxygen). Simulation of the effect of the acetylcholine interaction with the receptor site, by using a thermal bath, translates in an increase of the torsional flexibility of the acetoxy moiety.