Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design.
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.
Xu
Yechun
Y
Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
Colletier
Jacques Ph
JP
Jiang
Hualiang
H
Silman
Israel
I
Sussman
Joel L
JL
Weik
Martin
M
D000110:Acetylcholinesterase / Q000737:chemistry*; D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation / Q000187:drug effects*; D014101:Torpedo
D008024:Ligands; D000110:Acetylcholinesterase