![[ Electrostatic fluctuation around acetylcholinesterase (AChE) dimer ]](006.gif)
Electrostatic fluctuation around acetylcholinesterase (AChE) dimer
Stanislaw T. Wlodek
(University of Houston)
J. Andrew McCammon (University of
California, San Diego)
The correlation of electrostatic potentials between the crystal
structures of the wild type and the ``neutral mutant'' of
acetylcholinesterase (AChE). In the red region, the two types have
opposite sign; in the blue region, the two types have the same sign.
Animation of electrostatic potential variations during an MD
simulation of wild-type AChE (left); animation of
electrostatic potential variations during an MD simulation
of AChE ``neutral mutant'' (right).
The first animation shows the variations of the electrostatic
potential around the enzyme acetylcholinesterase that arise from the
thermal motion of the enzyme. The structural fluctuations of the enzyme
are from a molecular dynamics simulation [Wlodek et al., 1997]. The
electrostatic potential was determined for a series of snapshots from the
simulation by solution of the Poisson-Boltzmann equation with the UHBD software [Madura et
al., 1995]. The electrostatic calculations are for conditions of room
temperature, and physiologic ionic strength of 150 mM. The electrostatic
potential is in units of kcal/(mol e).
The calculations suggest that the regions of negative potential
(indicated with red) that surround the entrances to the two active sites
of the dimeric enzyme, are only marginally disturbed by protein motion.
The regions of positive potential appear to be significantly more
fluxional. The negative potential around the active sites of
acetylcholinesterase is known to contribute very substantially to the high
speed of the enzyme, by steering the positively-charged substrate
acetylcholine to the active sites [Radic et al., 1997]. The relative
stability of the regions of negative potential may therefore enhance the
effectiveness of this electrostatic steering.
This work was supported in part by grants from NSF, NIH,
and the San Diego Supercomputer Center.
Wlodek,
S.T., T.W. Clark, L.R. Scott, J.A. McCammon. Molecular Dynamics of
Acetylcholinesterase Dimer Complexed with Tacrine. J. Amer. Chem. Soc.
119, 9513-9522 (1997).
Madura, J.D., J.M. Briggs, R.C. Wade, M.E. Davis, B.A. Luty, A. Ilin,
J. Antosiewicz, M.K. Gilson, B. Bagheri, L.R. Scott, and J.A. McCammon.
Electrostatics and Diffusion of Molecules in Solution: Simulations with
the University of Houston Brownian Dynamics Program. Comp. Phys. Comm.
91, 57-95 (1995).
Radic, Z., P.D. Kirchhoff, D.M. Quinn, J.A. McCammon, P. Taylor.
Electrostatic Influence on the Kinetics of Ligand Binding to
Acetylcholinesterase: Distinctions Between Active Center Ligands and
Fasciculin. J. Biol. Chem. 272,
23265-23277 (1997).
McCammon Group, UCSD (http://mccammon.ucsd.edu/)
Created by Cameron Mura on Sat Jun 7 17:55:12 PDT 2003.
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