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Effects of Soman Inhibition and of Structural Differences on Cholinesterase Molecular Dynamics: A Neutron Scattering Study

F. Gabel ^*, M. Weik ^*, P. Masson , F. Renault , D. Fournier , L. Brochier , B. P. Doctor , A. Saxena , I. Silman ^¶ and G. Zaccai ^* ||

^* Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale, Grenoble, France; Centre de Recherches du Service de Santé des Armées, Unité d'Enzymologie, La Tronche, France; Institut de Pharmacologie et Biologie Structurale, Toulouse, France; Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, Maryland; ^¶ Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel; and ^|| Institut Laue-Langevin, Grenoble, France

Correspondence: Address reprint requests to Martin Weik, Institut de Biologie Structurale CEA-CNRS, 41 rue Jules Horowitz, F-38027 Grenoble Cedex 1, France. Tel.: 33-43-878-9569; E-mail: weik{at}ibs.fr.

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.