Induced fit in mouse acetylcholinesterase upon binding a femtomolar inhibitor: a molecular dynamics study

A molecular dynamics simulation of mouse acetylcholinesterase (mAChE) complexed with syn-TZ2PA6, a femtomolar AChE inhibitor, is compared to a simulation of unliganded mAChE. The simulation of the complex was initiated by placing the inhibitor in its bound conformation of the crystal complex into a structure of unliganded mAChE selected from preliminary protein-ligand docking results. During a 2 ns period, the enzyme subsequently displayed a substantial "induced fit" response to yield a conformation very similar to that obtained by crystallography (Bourne et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1449-1454). In this conformation of unique nature, the Trp 286 side chain of the enzyme flips out of the hydrophobic core and becomes highly solvent exposed. The imidazole ring of His 287 is almost orthogonal relative to its position in the unliganded enzyme, creating a stable pi stacking arrangement with the Trp 286 side chain. Other major deviations among the active site residues include side chain conformational changes of Trp 86, Tyr 133, Tyr 337, and Phe 338. These residues in the complex deviate from their positions in unliganded mAChE to better accommodate the inhibitor in the active site gorge.