Studying the roles of W86, E202, and Y337 in binding of acetylcholine to acetylcholinesterase using a combined molecular dynamics and multiple docking approach.

A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the roles of the anionic subsite residues (W86, E202, Y337) in the binding of acetylcholine (ACh) to acetylcholinesterase (AChE). We find that E202 stabilizes docking of ACh via electrostatic interactions. However, we find no significant electrostatic contribution from the aromatic residues. Docking energies of ACh to mutant AChE show a more pronounced effect because of size/shape complementarity. Mutating to smaller residues results in poorer binding, both in terms of docking energy and statistical docking probability. Besides separating out electrostatics by turning off the partial charges from each residue and comparing it with the native, the mutations in this study are W86F, W86A, E202D, E202Q, E202A, Y337F, and Y337A. We also find that all perturbations result in a significant reduction in binding of extended ACh in the catalytically productive orientation. This effect is primarily caused by a small shift in preferred position of the quaternary tail.