OPEN BACK DOOR IN A MOLECULAR-DYNAMICS SIMULATION OF ACETYLCHOLINESTERASE

The enzyme acetylcholinesterase generates a strong electrostatic field that can attract the cationic substrate acetylcholine to the active s ite. However, the long and narrow active site gorge seems inconsistent with the enzyme's high catalytic rate. A molecular dynamics simulatio n of acetylcholinesterase in water reveals the transient opening of a short channel, large enough to pass a water molecule, through a thin w all of the active site near tryptophan-84. This simulation suggests th at substrate, products, or solvent could move through this ''back door ,'' in addition to the entrance revealed by the crystallographic struc ture. Electrostatic calculations show a strong field at the back door, oriented to attract the substrate and the reaction product choline an d to repel the other reaction product, acetate. Analysis of the open b ack door conformation suggests a mutation that could seal the back doo r and thus test the hypothesis that thermal motion of this enzyme may open multiple routes of access to its active site.