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Simulation of charge-mutant acetylcholinesterases
J Antosiewicz1, J A McCammon, S T Wlodek
1Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla 92093-0365, USA.
Biochemistry
|April 4, 1995
Summary
Mutation studies on acetylcholinesterase suggest electrostatic steering plays a minor role. However, Brownian dynamics simulations indicate electrostatic fields significantly enhance catalytic rates for both wild-type and mutant enzymes.
Area of Science:
- Biochemistry
- Computational Biology
- Enzyme Kinetics
Background:
- Acetylcholinesterase (AChE) is crucial for neurotransmission.
- Previous studies mutated surface acidic residues, showing minimal impact on hydrolysis rates.
- This led to conclusions that AChE activity is not diffusion-controlled and electrostatics play a minor role.
Purpose of the Study:
- To investigate the role of electrostatic steering in acetylcholinesterase catalysis.
- To re-examine the interpretation of experimental mutation studies.
Main Methods:
- Brownian dynamics simulations were performed on Torpedo californica acetylcholinesterase.
- Surface acidic residues homologous to those mutated in human AChE were computationally neutralized.
Main Results:
- Simulated mutation effects on rate constants closely matched experimental findings.
- The enzyme's electrostatic field was found to increase catalytic rate constants by approximately tenfold for both wild-type and mutant enzymes.
Conclusions:
- Experimental mutation studies do not invalidate the significant role of electrostatic steering in acetylcholinesterase catalysis.
- Electrostatic interactions remain a critical factor influencing enzyme reaction rates.