AN ELECTROSTATIC MECHANISM FOR SUBSTRATE GUIDANCE DOWN THE AROMATIC GORGE OF ACETYLCHOLINESTERASE

Electrostatic calculations based on the recently solved crystal struct ure of acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7 ) indicate that this enzyme has a strong electrostatic dipole. The dip ole is aligned with the gorge leading to its active site, so that a po sitively charged substrate will be drawn to the active site by its ele ctrostatic field. Within the gorge, aromatic side chains appear to shi eld the substrate from direct interaction with most of the negatively charged residues that give rise to the dipole. The affinity of quatern ary ammonium compounds for aromatic rings, coupled with this electrost atic force, may work in concert to create a selective and efficient su bstrate-binding site in acetylcholinesterase and explain why the activ e site is situated at the bottom of a deep gorge lined with aromatic r esidues.