Molecular dynamics, density functional and second-order Møller-Plesset theory study of the structure and conformation of acetylcholine in vacuo and in solution

Abstract

Molecular mechanics minimizations based on the CVFF force ®eld and molecular dynamics simulation for a time of 2.5 ns were performed to examine the conformational behaviour and the molecular motion of acetylcholine in vacuo and in aqueous solution. Five low-lying conformations, namely the TT, TG, GG, G*G and GT, were obtained from molecular mechanics computations with the GT structure as the absolute minimum. Molecular dynamics trajectories in vacuo and in water show that only four (GT, GG, G*G and TG) and three (TG, TT and GT) conformations are present in the simulation time, respectively. Density functional B3LYP and second-order Mùller± Plesset (MP2) methods were then used to study all the ®ve lowest-lying conformers of acetylcholine neurotransmitter in vacuo and in water by the polarizable continuum model approach. The B3LYP and MP2 computations show that in the gas phase all minima lie in a narrow range of energy with the G*G conformer as the most stable one. The relative minima GG, GT, TG and TT are located at 1.1 (3.3), 1.8 (4.2), 2.1 (4.5) and 4.3 (7.3) kcal/mol above the absolute one at the B3LYP (MP2) level. The preferred conformation in water is the TG. Solvation reduces the relative energy dierences between the ®ve minima in both computations.

Ion Pairing of the Neurotransmitters Acetylcholine and Glutamate in Aqueous Solutions

“…The structure of ACh + cation is defined by a positively charged trimethylammonium (onium) group and a carbonyl group while the structure of Glu – is characterized by a positively charged ammonium group and two negatively charged carboxylate groups (Figure ). In relation to ACh + , only two of its conformers, TG and TT, are bioactive in living organisms with the TT and TG forms being recognized by muscarinic and nicotinic receptors, respectively. − , Both conformers are stable in a water environment, however, TG is more stable . The difference between them is determined by the dihedral angle, N + –C b2 –C b1 –O 7 , which is either in the trans- (∼180°) or gauche- (∼70°) positions (Figure a,b).…”

A Density-Functional Study of the Conformational Preference of Acetylcholine in the Neutral Hydrolysis

“…Therefore, the backbone and the tail must curl up in order to shorten the head-tail distance. Such curling behavior does not only exist in gas phase but also in solvent [18,20,23,27]. The gauche conformation at D2 and D3 meets the condition, particularly at D3, where the head-tail distance is the shortest.…”

“…The five ACh + conformers (tg * g, tgg, ttg, tgt, and ttt) are in the low-level group (Figure 3a-e), and the other two conformers (ctg and ctt) are in the high-level group (Figure 3f,g). Other computational studies [20,23,39,40] also conclude the stability of the five low-level conformers. It is important to note that our results support the experiments that observed ACh + (tg * g), (tgg), and (ttg) in their stable states [29,41,42].…”

“…The dependency is stronger when the reaction involves an enzyme as a catalyst [14,15]. In the ACh + case, at least three conformers have been investigated to understand their stability and the interconversion among the conformers and to explore the fluorination and solvent effects on each of them [16][17][18][19][20][21][22][23][24][25][26][27]. However, to the best of our knowledge, studies of ACh + conformers remain limited to its stability as an individual molecule.…”

Density Functional Theory Study on Conformers of Benzoylcholine Chloride

“…e determination of the minimum energy conformers of acetylcholine has been subject by many theoretical works [1][2][3]. Marino et al have investigated the conformational behavior and molecular motion of acetylcholine in vacuum and aqueous solution [4]. ey have calculated �ve low lying conformers by molecular mechanics computing.…”