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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
Author(s) -
Xu Yechun,
Colletier Jacques Ph.,
Jiang Hualiang,
Silman Israel,
Sussman Joel L.,
Weik Martin
Publication year - 2008
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.083453808
Subject(s) - acetylcholinesterase , molecular dynamics , chemistry , rational design , acetylcholinesterase inhibitor , docking (animal) , crystallography , crystal structure , stereochemistry , protein structure , computational chemistry , biophysics , enzyme , materials science , biochemistry , nanotechnology , biology , medicine , nursing
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.