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Science 4 March 1994:
Vol. 263. no. 5151, pp. 1276 - 1278
DOI: 10.1126/science.8122110
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Articles

Science, Vol 263, Issue 5151, 1276-1278
Copyright © 1994 by American Association for the Advancement of Science

articles

Open "back door" in a molecular dynamics simulation of acetylcholinesterase

MK Gilson, TP Straatsma, JA McCammon, DR Ripoll, CH Faerman, PH Axelsen, I Silman, and JL Sussman

Department of Chemistry, University of Houston, TX 77204-5641.

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


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