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Trapp M.,CNRS Institute of Pharmacology and Structural Biology | Trapp M.,French National Center for Scientific Research | Trapp M.,Joseph Fourier University | Trapp M.,Laue Langevin Institute | And 20 more authors.
Journal of Physical Chemistry B | Year: 2012

Enzymes are animated by a hierarchy of motions occurring on time scales that span more than 15 orders of magnitude from femtoseconds (10-15 s) to several minutes. As a consequence, an enzyme is characterized by a large number of conformations, so-called conformational substates that interconvert via molecular motions. The energy landscapes of these macromolecules are very complex, and many conformations are separated by only small energy barriers. Movements at this level are fast thermal atomic motions occurring on a time scale between 10-7 and 10-12 s, which are experimentally accessible by incoherent neutron scattering techniques. They correspond to local fluctuations within the molecule and are believed to act as coupling links for larger, conformational changes. Several questions related to this hierarchy of motions are a matter of very active research: which of the motions are involved in the biological functions of the macromolecule and are motions of different energy (and thus time) scale correlated? How does the distribution of motions change when an enzyme is inhibited? We report here on investigations of the enzyme human acetylcholinesterase, unliganded and in complex with the noncovalent inhibitor Huperzine A, by incoherent neutron scattering. Different time scales are explored to shed light on the interplay of enzyme activity, dynamics, and inhibition. Surprisingly the average molecular dynamics do not seem to be altered by the presence of the inhibitor used in this study within the considered time scales. The activation energy for the free and the inhibited form of the enzyme is moreover found to be almost identical despite changes of interactions inside the gorge, which leads to the active site of the enzyme. © 2012 American Chemical Society.


Trapp M.,Helmholtz Center Berlin | Tehei M.,University of Wollongong | Tehei M.,Australian Institute of Nuclear Science and Engineering AINSE | Trovaslet M.,CNRS Institute of Pharmacology and Structural Biology | And 12 more authors.
Journal of the Royal Society Interface | Year: 2014

It is a long debated question whether catalytic activities of enzymes, which lie on the millisecond timescale, are possibly already reflected in variations in atomic thermal fluctuations on the pico- to nanosecond timescale. To shed light on this puzzle, the enzyme human acetylcholinesterase in its wild-type form and complexed with the inhibitor huperzine Awere investigated by various neutron scattering techniques and molecular dynamics simulations. Previous results on elastic neutron scattering at various timescales and simulations suggest that dynamical processes are not affected on average by the presence of the ligand within the considered time ranges between 10 ps and 1 ns. In the work presented here, the focus was laid on quasi-elastic (QENS) and inelastic neutron scattering (INS). These techniques give access to different kinds of individual diffusive motions and to the density of states of collective motions at the sub-picoseconds timescale. Hence, they permit going beyond the first approach of looking at mean square displacements. For both samples, the autocorrelation function was well described by a stretched-exponential function indicating a linkage between the timescales of fast and slow functional relaxation dynamics. The findings of the QENS and INS investigation are discussed in relation to the results of our earlier elastic incoherent neutron scattering and molecular dynamics simulations. © 2014 The Author(s) Published by the Royal Society.


Peters J.,Joseph Fourier University | Peters J.,Laue Langevin Institute | Peters J.,CNRS Institute of Pharmacology and Structural Biology | Trovaslet M.,Institute Of Recherches Biomedicales Des Armees | And 15 more authors.
Physical Chemistry Chemical Physics | Year: 2012

The temperature dependence of the dynamics of recombinant human acetylcholinesterase (hAChE) and plasma human butyrylcholinesterase (hBChE) is examined using elastic incoherent neutron scattering. These two enzymes belong to the same family and present 50% amino acid sequence identity. However, significantly higher flexibility and catalytic activity of hAChE when compared to the ones of hBChE are measured. At the same time, the average height of the potential barrier to the motions is increased in the hBChE, e.g. more thermal energy is needed to cross it in the latter case, which might be the origin of the increase in activation energy and the reduction in the catalytic rate of hBChE observed experimentally. These results suggest that the motions on the picosecond timescale may act as a lubricant for those associated with activity occurring on a slower millisecond timescale. © 2012 the Owner Societies.


Trapp M.,University of Heidelberg | Trapp M.,Helmholtz Center Berlin | Marion J.,CNRS Institute of Pharmacology and Structural Biology | Marion J.,Laue Langevin Institute | And 8 more authors.
Physical Chemistry Chemical Physics | Year: 2013

The effects of high hydrostatic pressure on the structure and dynamics of model membrane systems were investigated using neutron scattering. Diffraction experiments show shifts of the pre- and main-phase transitions of multilamellar vesicles of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) to higher temperatures with increased pressure which are close to results observed previously by other techniques, namely (10.4 ± 1.0) K kbar-1 and (20.0 ± 0.5) K kbar-1 for the two transitions. Backscattering spectroscopy reveals that the mean square displacements in the liquid phase are about 10% smaller at 300 bar and about 20% smaller at 600 bar compared to atmospheric pressure, whereas in the gel phase below the main phase transition the mean square displacements show a smaller difference in the dynamics of the three pressure values within the studied pressure range. © 2013 the Owner Societies.


Styles M.J.,University of Melbourne | Riley D.P.,University of Melbourne | Riley D.P.,Australian Institute of Nuclear Science and Engineering AINSE
Journal of Physics: Conference Series | Year: 2010

In an effort to mitigate the expense and broaden the applicability of customised environment chambers, researchers at the University of Melbourne and the Australian Nuclear Science and Technology Organisation (ANSTO) have designed and are currently commissioning a modular reaction chamber, capable of separating the necessities of diffraction methodologies from those of the desired sample environment. The In Situ Reaction Chamber (ISRC) abstracts many of the details intrinsic to the diffractometer, allowing users to design inexpensive environmental inserts that may be readily customised to their individual needs. The first insert to be developed for use with the ISRC is a high temperature furnace capable of providing an oxidising sample environment up to 1600°C. © 2010 IOP Publishing Ltd.

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