Acetylcholine Conformational Flexibility and Its Neutral Hydrolysis in Aqueous Solution

Enzymatic hydrolysis is the main target to deal with ACh depletion. However, a recent study indicates that the non-enzymatic one may contribute to the depletion. This study highlights the necessity of considering possible conformers, discrete-continuum models, and dispersive effects for investigating the neutral (non-enzymatic) hydrolysis of flexible molecules in aqueous solution. We systematically built the possible conformers within the first-principles framework. The results confirm the reactivity of high-energy ACh conformer towards neutral hydrolysis. We proposed that conformational changes occur before the hydrolysis. The calculated activation and reaction energy shows that the discrete-continuum solvation model gives the closest result to experimental observations. This study also shows that neglecting dispersive effects brings unreliable structures in the initial state, which leads to unreliable activation energy.