Selective modulation of alkali metal ions on acetylcholinesterase

Acetylcholinesterase (AChE) is an important hydrolase in cholinergic synapses and a candidate target in the treatment of Alzheimer's disease. The lithium treatment widely used in neurological disorders can alter the AChE activity, yet the underlying mechanism of how the ion species regulate the enzymatic activity remains unclear. In this work, we performed combined quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations and well-tempered metadynamics to understand the modulation of human AChE (hAChE) activity using three alkali metal ions (Li⁺, Na⁺, and K⁺) in different concentrations. Our simulations show that the binding affinity and catalytic activity are affected by different ion species through allosteric ion coordination geometries on the hAChE complex and distant electrostatic screening effect. A Li⁺ cluster involving D330, E393, and D397 residues and three Li⁺ ions was found to be highly conserved and can be critical to the enzyme activity. Binding energy calculations indicate that the electrostatic screening from allosterically bound cations can affect the key residues at the catalytic site and active-site gorge, including E199. Furthermore, an increase in ion concentration can lead to lower reactivity, especially for Li⁺ ions, which exhibit more cation-hAChE contacts than Na⁺ and K⁺. The selective ion binding and their preferred modulation on hAChE are highly related to ion species. This work provides a molecular perspective on selective modulation by different ion species of the enzyme catalytic processes.