The Versatile Behavior of Acetylcholine

Our first exploration of property space was focused on acetylcholine. This molecule was chosen for its interesting structure, major biological role, and the abundant data available on its conformational properties [15]. The behavior of acetylcholine was analyzed by MD simulations in vacuum, in isotropic media (water and chloroform) [16] and in an anisotropic medium, i.e. a membrane model [17]. Hydrated n-octanol (Imol water/4mol octanol) was also used to represent a medium structurally intermediate between a membrane and the isotropic solvents [17]. 

The conformational profile of acetylcholine depended on the T2 and T3 dihedral angles since Tj and T4 remained constant during all monitored simulations (Fig. 1.4). It was found that acetylcholine assumes seven low-energy conformations 

Notwithstanding this. Table 1.2 clearly shows that the behavior of acetylchoHne reflected the physicochemical properties of the simulated media by adapting its property space. This is particularly evident when examining the Hpophilicity averages, since the polarity of acetylcholine increased in aU media compared to vacuum although the differences between the mean log P values were small, they were significant as assessed by their 99.9% confidence Hmits. 

1 In each box, the first line shows the limits (minimum to maximum value), the second line the range and the third line the mean 99.9% confidence limits (t-test). The compiled results are from [16,17). 

Conversely, in a membrane model, acetylcholine showed mean log P values very similar to those exhibited in water. This was due to the compound remaining in the vicinity of the polar phospholipid heads, but the disappearance of extended forms decreased the average log P value somewhat. This suggests that an anisotropic environment can heavily modify the conformational profile of a solute, thus selecting the conformational clusters more suitable for optimal interactions. In other words, isotropic media select the conformers, whereas anisotropic media select the conformational clusters. The difference in conformational behavior in isotropic versus anisotropic environments can be explained considering that the physicochemical effects induced by an isotropic medium are homogeneously uniform around the solute so that all conformers are equally influenced by them. In contrast, the physicochemical effects induced by an anisotropic medium are not homogeneously distributed and only some conformational clusters can adapt to them. 

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