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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.

Xu Y, Colletier JP, Jiang H, Silman I, Sussman JL, Weik M

Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.

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.

Published 24 March 2008 in Protein Sci, 17(4): 601-5.
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