Ionic Hydrogen Bonds in Bioenergetics. 4. Interaction Energies of Acetylcholine with Aromatic and Polar Molecules

Abstract

The binding energies of the quaternary ions (CH3)4N+ and acetylcholine (ACh) to neutral molecules have been measured by pulsed high-pressure mass spectrometry and calculated ab initio, to model interactions in the acetylcholine receptor channel. Binding energies to C6H6 and C6H5CH3 are similar to those to H2O (33−42 kJ/mol (8−10 kcal/mol)), but are weaker than those to polar organic ligands such as CH3CO2CH3 (50−63 kJ/mol (12−15 kcal/mol)) and to amides (up to 84 kJ/mol (20 kcal/mol)). These data suggest that aromatic residues that line the groove leading to the ACh receptor site may provide stabilization comparable to water, and therefore allow entry from the aqueous environment, yet do not bind ACh as strongly as polar protein groups, and therefore allow transit, without trapping, to the receptor site. Four of the five distinct ACh conformers located computationally are stabilized by internal C−H···O hydrogen bonds involving the quaternary ammonium group, which is supported by the thermochemistry of the protonated analogue, CH3CO2CH2CH2N(CH3)2H+, and by the measured bonding energy between models of the ACh end groups, (CH3)4N+ and CH3CO2CH3. Each conformer forms a number of stable complexes with water or benzene. Several possible roles for an ACh conformational change upon entry into the channel are discussed, including partial compensation for the loss of bulk solvation. An additional role for the aromatic environment is also suggested, namely lowering the energy barrier to the formation of the active all-trans ACh rotamer required at the receptor site.

How does acetylcholine lose trimethylamine? A density functional theory study of four competing mechanisms

“…In addition, two isomers having cis-carbonyl arrangement were located at higher energies (see structures ACh06 and ACh07 in Supplementary Figure S2, which can be found in the electronic version of this article). Structures ACh01-ACh05 closely correspond to five low-energy structures (differing by only 4.5 kcal mol Ϫ1 ) identified by Deakyne and Meot-Ner on the HF/6-31G(d) PES [24]. Similarly, Seydou et al [25] also reported five low-energy conformers at the B3PW91/6-311ϩϩG(d,p) level of theory, which closely correspond to ACh01-ACh05.…”

Theoretical Investigations of Acetylcholine (ACh) and Acetylthiocholine (ATCh) Using ab Initio and Effective Fragment Potential Methods

“…This is consistent with previous DFT and MP2 calculations. 2 It also shows the importance of the inclusion of dynamic electron correlation, as in the case of the binding of benzene with N(CH 3 ) 4 + . [62][63][64] To more fully evaluate the effect of dynamic electron correlation on the relative energies, gg′ and gg were also optimized at the MP2/6-31G(d) level.…”

“…Fully optimized structures of ACh, ACh(H 2 O), and ACh(H 2 O) 2 were computed at the HF/6-31G(d) level using the GAMESS electronic structure package. A large number of equilibrium structures were located and characterized as minima by a harmonic normal-mode analysis.…”

“…19 Computational studies have employed ab initio, 2,35,[38][39][48][49][50] semiempirical, and empirical methods, [30][31][32][33][34][42][43][44][45] as well as molecular dynamics. [40][41]52 However, despite the large number of reported works, several issues remain unresolved.…”

“…2 In this notation, the first and second letters refer to the N 1 C 5 C 6 O 7 and C 5 C 6 O 7 C 8 dihedral angles, respectively. The gg′ conformation was predicted to be the most stable rotamer.…”