Gallery of Biomolecular Simulations
Reaction gorge fluctuation in acetylcholinesterase
GIF (3.1M) animations. ]
Stanislaw T. Wlodek
(University of Houston)
J. Andrew McCammon (University of
California, San Diego)
The animation is also available as a Java applet.
This animation shows the "breathing" motions of the gorge or channel
that leads from the region outside the enzyme acetylcholinesterase (AChE),
to the active site. These fluctuations in the width of the channel are
required to allow the substrate acetylcholine (ACh) to move from the
outside into the active site. They also contribute to the selectivity of
the enzyme, by slowing the entrance of substrates that are larger than
ACh. This animation is composed of 75 frames set up to loop for 1,000
The outer entrance to the channel is at the top in this animation, and
the active site chamber, with key amino acid residues shown in blue, is at
the bottom. The structures are from a 750 ps molecular dynamics
et al., 1997). The surface of the channel defines the volume
that is accessible to a probe of radius 0.14 nm, about the size of a
water molecule. The bottleneck region midway down the channel is formed
by aromatic residues including Phe 290 and Tyr 334, shown in
purple. This bottleneck is almost always closed to the substrate ACh,
which can be approximated by a probe of radius 0.24 nm.
Nevertheless, the fluctuations in the width of the bottleneck allow ACh to
successfully enter the active site almost every time an ACh molecule moves
into the outer part of the channel. Substrates that are even a little bit
larger than ACh are much less likely to be admitted before they escape
back to the outside, because the bottleneck opens less frequently for
larger substrates. Thus, the enzyme exhibits ``dynamic selectivity'' in
its binding of substrates (Zhou et al., 1998).
Joel Sussman kindly provided the crystallographic coordinates that
were used to start the simulation (Harel et al., 1993), and are
available from the Protein Data Bank (PDB) code: 1ACJ).
Jim Briggs and Paul de Bakker helped in the preparation of this animation.
This work was supported in part by grants from NSF,
NIH, and the San Diego Supercomputer Center.
S.T., Clark, T.W., Scott L.R., McCammon J.A. Molecular Dynamics of
Acetylcholinesterase Dimer Complexed with Tacrine. J. Amer. Chem. Soc.
119, 9513-9522 (1997)
Zhou, H.X., Wlodek, S.T., McCammon, J.A. Conformation Gating as a
Mechanism for Enzyme Specificity. Proc.
Natl. Acad. Sci. USA 95, 9280-9283 (1998)
Harel, M., Schalk, I., Ehret-Sabatier, L., Bouet, F., Goeldner, M.,
Hirth, C., Axelsen, P., Silman, I., Sussman, J.L. Quaternary Ligand
Binding to Aromatic Residues in the Active-site Gorge of
Acetylcholinesterase. Proc. Natl. Acad. Sci. USA 90, 9031-9035
McCammon Group, UCSD (http://mccammon.ucsd.edu/)
Created by Cameron Mura on Sat Jun 7 17:55:12 PDT 2003.
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