Simulation of charge-mutant acetylcholinesterases.
A recent experimental study of human acetylcholinesterase has shown that the mutation of surface acidic residues has little effect on the rate constant for hydrolysis of acetylthiocholine. It was concluded, on this basis, that the reaction is not diffusion controlled and that electrostatic steering plays only a minor role in determining the rate. Here we examine this issue through Brownian dynamics simulations on Torpedo californica acetylcholinesterase in which the surface acidic residues homologous with those mutated in the human enzyme are artificially neutralized. The computed effects of the mutations on the rate constants reproduce quite well the modest effects of the mutations upon the measured encounter rates. Nonetheless, the electrostatic field of the enzyme is found to increase the rate constants by about an order of magnitude in both the wild type and the mutants. We therefore conclude that the mutation experiments do not disprove that electrostatic steering substantially affects the catalytic rate of acetylcholinesterase.
Antosiewicz
J
J
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla 92093-0365, USA.
McCammon
J A
JA
Wlodek
S T
ST
Gilson
M K
MK
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000122:Acetylthiocholine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004563:Electrochemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D009994:Osmolar Concentration; D013329:Structure-Activity Relationship; D014101:Torpedo
D000122:Acetylthiocholine; D000110:Acetylcholinesterase