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Protein Science (2008), 17:601-605. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design

Yechun Xu1,2,6, Jacques Ph. Colletier3,6,7, Hualiang Jiang4,5, Israel Silman2, Joel L. Sussman1, and Martin Weik3

1 Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel
2 Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel
3 Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale, Jean Pierre Ebel, CEA-CNRS, Université Joseph Fourier, F-38027 Grenoble, France
4 Center for Drug Discovery and Design, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
5 School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

(RECEIVED January 15, 2008; FINAL REVISION January 24, 2008; ACCEPTED January 24, 2008)

Crystal structures of acetylcholinesterase complexed with ligands are compared with side-chain conformations accessed by native acetylcholinesterase in molecular dynamics (MD) simulations. Several crystallographic conformations of a key residue in a specific binding site are accessed in a simulation of native acetylcholinesterase, although not seen in rotomer plots. Conformational changes upon ligand binding thus involve preexisting equilibrium dynamics. Consequently, rational drug design could benefit significantly from conformations monitored by MD simulations of native targets.

Keywords: X-ray crystallography; protein dynamics; conformational energy landscape; ligand binding; structure-based drug design; molecular dynamics simulation; acetylcholinesterase


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Y. Xu, J.-P. Colletier, M. Weik, H. Jiang, J. Moult, I. Silman, and J. L. Sussman
Flexibility of Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase: X-ray versus Molecular Dynamics
Biophys. J., September 1, 2008; 95(5): 2500 - 2511.
[Abstract] [Full Text] [PDF]


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