title: Effects of soman inhibition and of structural differences on cholinesterase molecular dynamics: a neutron scattering study.
abstract: Incoherent elastic neutron scattering experiments on members of the cholinesterase family were carried out to investigate how molecular dynamics is affected by covalent inhibitor binding and by differences in primary and quaternary structure. Tetrameric native and soman-inhibited human butyrylcholinesterase (HuBChE) as well as native dimeric Drosophila melanogaster acetylcholinesterase (DmAChE) hydrated protein powders were examined. Atomic mean-square displacements (MSDs) were found to be identical for native HuBChE and for DmAChE in the whole temperature range examined, leading to the conclusion that differences in activity and substrate specificity are not reflected by a global modification of subnanosecond molecular dynamics. MSDs of native and soman-inhibited HuBChE were identical below the thermal denaturation temperature of the native enzyme, indicating a common mean free-energy surface. Denaturation of the native enzyme is reflected by a relative increase of MSDs consistent with entropic stabilization of the unfolded state. The results suggest that the stabilization of HuBChE phosphorylated by soman is due to an increase in free energy of the unfolded state due to a decrease in entropy.
authors.affiliation: Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale, 41 rue Jules Horowitz, F-38027 Grenoble Cedex 1, France.
authors.forename: F
authors.initials: F
authors.lastname: Gabel
authors.forename: M
authors.initials: M
authors.lastname: Weik
authors.forename: P
authors.initials: P
authors.lastname: Masson
authors.forename: F
authors.initials: F
authors.lastname: Renault
authors.forename: D
authors.initials: D
authors.lastname: Fournier
authors.forename: L
authors.initials: L
authors.lastname: Brochier
authors.forename: B P
authors.initials: BP
authors.lastname: Doctor
authors.forename: A
authors.initials: A
authors.lastname: Saxena
authors.forename: I
authors.initials: I
authors.lastname: Silman
authors.forename: G
authors.initials: G
authors.lastname: Zaccai
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D002091:Butyrylcholinesterase / Q000737:chemistry; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000737:chemistry*; D002942:Circular Dichroism; D019281:Dimerization; D004331:Drosophila melanogaster; D019277:Entropy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D006859:Hydrogen; D015233:Models, Statistical; D009502:Neutrons; D016011:Normal Distribution; D010766:Phosphorylation; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D012542:Scattering, Radiation; D012999:Soman / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors; D014466:Ultraviolet Rays; D014867:Water / Q000737:chemistry
chemical_list: D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D014867:Water; D006859:Hydrogen; D012999:Soman; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases