Theoretical Study on the Conformational Bioeffect of the Fluorination of Acetylcholine

There has been an increasing interest in the study of fluorinated derivatives of gamma‐aminobutyric acid (GABA), an acetylcholine (AC) analog. This work reports a theoretical study on the effect of an α‐carbonyl fluorination in AC, aiming at understanding the role of a distant fluorine relative to the positively charged nitrogen on the conformational folding of the resulting fluorinated AC. In addition, the chemical and structural changes were evaluated on the basis of ligand‐enzyme (acetylcholinesterase) interactions. In an enzyme‐free environment, the fluorination yields conformational changes relative to AC due to the appearance of some attractive interactions with fluorine and a weaker steric repulsion between the fluorine substituent and the carboxyl group, rather than to a possible electrostatic interaction F⋅⋅⋅N+. Moreover, the gauche orientation in the N−C−C−O fragment of AC owing to the electrostatic gauche effect is reinforced after fluorination. For instance, the conformational equilibrium in AC is described by a competition between gauche and anti conformers (accounting for the N−C−C−O dihedral angle) in DMSO, while the population for a gauche conformer in the fluorinated AC is almost 100 % in both gas phase and DMSO. However, this arrangement is disrupted in the biological environment even in the fluorinated derivative (whose bioconformation‐like geometry shows a ligand‐protein interaction of −84.1 kcal mol−1 against −79.5 kcal mol−1 for the most stable enzyme‐free conformation), which shows an anti N−C−C−O orientation, because the enzyme induced‐fit takes place. Nevertheless, the most likely bioconformation for the fluorinated AC does not match the bioactive AC backbone nor the most stable enzyme‐free conformation, thus revealing the role of fluorination on the bioconformational control of AC.