Correlation of the dynamics of native human acetylcholinesterase and its inhibited huperzine A counterpart from sub-picoseconds to nanoseconds

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 A were 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.

[1]  M. W. van der Kamp,et al.  Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology. , 2013, Biochemistry.

[2]  P. Masson,et al.  Relation between dynamics, activity and thermal stability within the cholinesterase family. , 2013, Chemico-biological interactions.

[3]  B. P. Doctor,et al.  Structural analogs of huperzine A improve survival in guinea pigs exposed to soman. , 2013, Bioorganic & medicinal chemistry letters.

[4]  Jing Chen,et al.  Free energy landscape for the binding process of Huperzine A to acetylcholinesterase , 2013, Proceedings of the National Academy of Sciences.

[5]  P. Masson,et al.  Energy landscapes of human acetylcholinesterase and its Huperzine A-inhibited counterpart. , 2012, The journal of physical chemistry. B.

[6]  M. Rudolph,et al.  Structures of human acetylcholinesterase in complex with pharmacologically important ligands. , 2012, Journal of medicinal chemistry.

[7]  P. Masson,et al.  Activity and molecular dynamics relationship within the family of human cholinesterases. , 2012, Physical chemistry chemical physics : PCCP.

[8]  P. Renard,et al.  Huprine Derivatives as Sub‐Nanomolar Human Acetylcholinesterase Inhibitors: From Rational Design to Validation by X‐ray Crystallography , 2012, ChemMedChem.

[9]  A. Nemukhin,et al.  Correlation between the substrate structure and the rate of acetylcholinesterase hydrolysis modeled with the combined quantum mechanical/molecular mechanical studies. , 2010, Chemico-biological interactions.

[10]  J. Sussman,et al.  Acetylcholinesterase: from 3D structure to function. , 2010, Chemico-biological interactions.

[11]  John R. D. Copley,et al.  DAVE: A Comprehensive Software Suite for the Reduction, Visualization, and Analysis of Low Energy Neutron Spectroscopic Data , 2009, Journal of research of the National Institute of Standards and Technology.

[12]  J. Colmenero,et al.  Characterization of the "simple-liquid" state in a polymeric system: coherent and incoherent scattering functions. , 2009, Physical review. E, Statistical, nonlinear, and soft matter physics.

[13]  C. De Michele,et al.  Universal divergenceless scaling between structural relaxation and caged dynamics in glass-forming systems. , 2009, The Journal of chemical physics.

[14]  J. Swenson,et al.  Dynamics of a protein and its surrounding environment: a quasielastic neutron scattering study of myoglobin in water and glycerol mixtures. , 2009, The Journal of chemical physics.

[15]  G M Artmann,et al.  Hemoglobin dynamics in red blood cells: correlation to body temperature. , 2008, Biophysical journal.

[16]  J. Sussman,et al.  Acetylcholinesterase: how is structure related to function? , 2008, Chemico-biological interactions.

[17]  Hualiang Jiang,et al.  Induced‐fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure‐based drug design , 2008, Protein science : a publication of the Protein Society.

[18]  D. Kern,et al.  Dynamic personalities of proteins , 2007, Nature.

[19]  K. Hinsen,et al.  Fractional Brownian dynamics in proteins. , 2004, The Journal of chemical physics.

[20]  Torsten Becker,et al.  Direct determination of vibrational density of states change on ligand binding to a protein. , 2004, Physical review letters.

[21]  Jeremy C. Smith,et al.  The role of dynamics in enzyme activity. , 2003, Annual review of biophysics and biomolecular structure.

[22]  Yvain Nicolet,et al.  Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products* , 2003, Journal of Biological Chemistry.

[23]  Joel L Sussman,et al.  How does huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations. , 2003, Journal of the American Chemical Society.

[24]  C. Geula,et al.  Neurobiology of butyrylcholinesterase , 2003, Nature Reviews Neuroscience.

[25]  Kaihsu Tai,et al.  Molecular dynamics of acetylcholinesterase. , 2002, Accounts of chemical research.

[26]  J A McCammon,et al.  Molecular dynamics of mouse acetylcholinesterase complexed with huperzine A. , 1999, Biopolymers.

[27]  J A McCammon,et al.  Mouse acetylcholinesterase unliganded and in complex with huperzine A: a comparison of molecular dynamics simulations. , 1999, Biopolymers.

[28]  J. Mccammon,et al.  Conformation gating as a mechanism for enzyme specificity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  C. T. Moynihan,et al.  Correlation between the Activation Energies for Ionic Conductivity for Short and Long Time Scales and the Kohlrausch Stretching Parameter β for Ionically Conducting Solids and Melts , 1998 .

[30]  S. H. Chen,et al.  Dynamics of hydration water in protein , 1992 .

[31]  A. Goldman,et al.  Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein , 1991, Science.

[32]  S Cusack,et al.  Inelastic neutron scattering analysis of picosecond internal protein dynamics. Comparison of harmonic theory with experiment. , 1988, Journal of molecular biology.

[33]  D. Quinn,et al.  Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states , 1987 .

[34]  Bernard R. Brooks,et al.  Inelastic neutron scattering analysis of low frequency motion in proteins: A normal mode study of the bovine pancreatic trypsin inhibitor , 1986 .

[35]  Jia-sen Liu,et al.  The structures of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity , 1986 .

[36]  P. L. Hall,et al.  Incoherent neutron scattering functions for random jump diffusion in bounded and infinite media , 1981 .

[37]  A. Dianoux,et al.  Neutron incoherent scattering law for diffusion in a potential of spherical symmetry: general formalism and application to diffusion inside a sphere , 1980 .

[38]  K. S. Singwi,et al.  Theory of Slow Neutron Scattering by Liquids. I , 1962 .

[39]  K. S. Singwi,et al.  Diffusive Motions in Water and Cold Neutron Scattering , 1960 .

[40]  A. Erdélyi,et al.  Higher Transcendental Functions , 1954 .

[41]  Hay Dvira,et al.  Acetylcholinesterase : From 3 D structure to function , 2010 .

[42]  L. Larini,et al.  Universal scaling between structural relaxation and vibrational dynamics in glass-forming liquids and polymers , 2008 .

[43]  G. Kneller,et al.  Quasielastic neutron scattering and relaxation processes in proteins: analytical and simulation-based models. , 2005, Physical chemistry chemical physics : PCCP.

[44]  S. Cannistraro,et al.  Incoherent neutron scattering of copper azurin: a comparison with molecular dynamics simulation results , 1999, European Biophysics Journal.

[45]  N. Dencher,et al.  Molecular motions and hydration of purple membranes and disk membranes studied by neutron scattering , 1998, European Biophysics Journal.

[46]  D. Richard,et al.  Analysis and Visualisation of Neutron-Scattering Data , 1996 .

[47]  G. Careri,et al.  Protein hydration and function. , 1991, Advances in protein chemistry.

[48]  M. Bee,et al.  Quasielastic Neutron Scattering, Principles and Applications in Solid State Chemistry, Biology and Materials Science , 1988 .

[49]  J. Mccammon,et al.  Dynamics of Proteins and Nucleic Acids , 2018 .

[50]  Graham Williams,et al.  Non-symmetrical dielectric relaxation behaviour arising from a simple empirical decay function , 1970 .