Simulation study of the structure and dynamics of the Alzheimer's amyloid peptide congener in solution.

The amyloid Abeta(10-35)-NH2 peptide is simulated in an aqueous environment on the nanosecond time scale. One focus of the study is on the validation of the computational model through a direct comparison of simulated statistical averages with experimental observations of the peptide's structure and dynamics. These measures include (1) nuclear magnetic resonance spectroscopy-derived amide bond order parameters and temperature-dependent H(alpha) proton chemical shifts, (2) the peptide's radius of gyration and end-to-end distance, (3) the rates of peptide self-diffusion in water, and (4) the peptide's hydrodynamic radius as measured by quasielastic light scattering experiments. A second focus of the study is the identification of key intrapeptide interactions that stabilize the central structural motif of the peptide. Particular attention is paid to the structure and fluctuation of the central LVFFA hydrophobic cluster (17-21) region and the VGSN turn (24-27) region. There is a strong correlation between preservation of the structure of these elements and interactions between the cluster and turn regions in imposing structure on the peptide monomer. The specific role of these interactions in relation to proposed mechanisms of amyloidosis is discussed.

[1]  Peter T. Lansbury,et al.  A REDUCTIONIST VIEW OF ALZHEIMER'S DISEASE , 1996 .

[2]  H. Vinters,et al.  Point Substitution in the Central Hydrophobic Cluster of a Human β-Amyloid Congener Disrupts Peptide Folding and Abolishes Plaque Competence† , 1996 .

[3]  D. Kirschner,et al.  On the nucleation and growth of amyloid beta-protein fibrils: detection of nuclei and quantitation of rate constants. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Jim Glosli,et al.  Comments on P3M, FMM, and the Ewald method for large periodic Coulombic systems , 1996 .

[5]  D. Walsh,et al.  Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. , 1997, The Journal of biological chemistry.

[6]  William M. Gelbart,et al.  Counterion-Induced Attraction between Rigid Polyelectrolytes , 1997 .

[7]  J. Hoh,et al.  Cationic silanes stabilize intermediates in DNA condensation , 1999, FEBS letters.

[8]  A. Szabó,et al.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 2. Analysis of experimental results , 1982 .

[9]  P. Lansbury,et al.  Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-beta protein. , 1997, Chemistry & biology.

[10]  G. Grest,et al.  Dynamics of entangled linear polymer melts: A molecular‐dynamics simulation , 1990 .

[11]  G. Wagner,et al.  Frequency spectrum of NH bonds in eglin c from spectral density mapping at multiple fields. , 1995, Biochemistry.

[12]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[13]  Giovanni Lipari,et al.  MODEL-FREE APPROACH TO THE INTERPRETATION OF NUCLEAR MAGNETIC RESONANCE RELAXATION IN MACROMOLECULES. 1. THEORY AND RANGE OF VALIDITY , 1982 .

[14]  George B. Benedek,et al.  Temperature dependence of amyloid β-protein fibrillization , 1998 .

[15]  M. Philippopoulos,et al.  Internal Motions in the Molecular Tumbling Regime. Effect on NMR Dipolar Cross-Relaxation and Interproton Distance Determination , 1994 .

[16]  Ron Elber,et al.  MOIL-View - A Program for Visualization of Structure and Dynamics of Biomolecules and STO - A Program for Computing Stochastic Paths , 1995 .

[17]  Peter T. Lansbury,et al.  Observation of metastable Aβ amyloid protofibrils by atomic force microscopy , 1997 .

[18]  D. Eisenberg,et al.  Atomic solvation parameters applied to molecular dynamics of proteins in solution , 1992, Protein science : a publication of the Protein Society.

[19]  J. Hansen,et al.  Statistical mechanics of simple coulomb systems , 1980 .

[20]  J R Ghilardi,et al.  Activation barriers to structural transition determine deposition rates of Alzheimer's disease a beta amyloid. , 2000, Journal of structural biology.

[21]  S. Fujime,et al.  [Dynamic light-scattering]. , 1985, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[22]  J. Neu.  Wall-Mediated Forces between Like-Charged Bodies in an Electrolyte , 1999 .

[23]  N Casey,et al.  Residual structure in the Alzheimer's disease peptide: probing the origin of a central hydrophobic cluster. , 1998, Folding & design.

[24]  J R Ghilardi,et al.  In vitro growth of Alzheimer's disease beta-amyloid plaques displays first-order kinetics. , 1996, Biochemistry.

[25]  Charles M. Lieber,et al.  Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. , 1997, Chemistry & biology.

[26]  V. Bloomfield,et al.  Condensation of DNA by multivalent cations: Considerations on mechanism , 1991, Biopolymers.

[27]  J R Ghilardi,et al.  1H NMR of A beta amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence. , 1995, Biochemistry.

[28]  M. Falk,et al.  Interactions between charged spherical macroions , 1996 .

[29]  T. Schneider,et al.  Molecular-dynamics study of a three-dimensional one-component model for distortive phase transitions , 1978 .

[30]  A. Szabó,et al.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 1. Theory and range of validity , 1982 .

[31]  P. Pincus,et al.  Counterion-Condensation-Induced Collapse of Highly Charged Polyelectrolytes , 1998 .

[32]  George B. Benedek,et al.  Kinetic theory of fibrillogenesis of amyloid β-protein , 1997 .

[33]  D. Chan,et al.  Long-Range Electrostatic Attractions between Identically Charged Particles in Confined Geometries: An Unresolved Problem. , 1999, Journal of colloid and interface science.

[34]  Gerald S. Manning,et al.  Limiting Laws and Counterion Condensation in Polyelectrolyte Solutions I. Colligative Properties , 1969 .

[35]  D. Teplow,et al.  Structural and kinetic features of amyloid beta-protein fibrillogenesis. , 1998, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[36]  G. Lipari.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules , 1982 .

[37]  A. Lyubartsev,et al.  Monte Carlo Simulation Study of DNA Polyelectrolyte Properties in the Presence of Multivalent Polyamine Ions , 1997 .

[38]  D. V. Kuznetsov,et al.  Chain Collapse and Counterion Condensation in Dilute Polyelectrolyte Solutions , 1998, cond-mat/9802292.

[39]  Kremer,et al.  Structure of salt-free linear polyelectrolytes. , 1993, Physical review letters.

[40]  Hiroshi Noguchi,et al.  Morphological variation in a collapsed single homopolymer chain , 1998 .

[41]  P. Mantyh,et al.  Brain Amyloid — A Physicochemical Perspective , 1996, Brain pathology.

[42]  Joshua Jortner,et al.  Modelling of Biomolecular Structures and Mechanisms , 1995 .

[43]  G. Wagner,et al.  Mapping of the spectral densities of N-H bond motions in eglin c using heteronuclear relaxation experiments. , 1992, Biochemistry.

[44]  R W Hockney,et al.  Computer Simulation Using Particles , 1966 .

[45]  P. Lansbury,et al.  Amyloid fibrillogenesis: themes and variations. , 2000, Current opinion in structural biology.

[46]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[47]  Andrea J. Liu,et al.  Counterion-Mediated Attraction between Two Like-Charged Rods , 1997 .

[48]  B. Lee,et al.  The interpretation of protein structures: estimation of static accessibility. , 1971, Journal of molecular biology.

[49]  C. Barrow,et al.  Solution conformations and aggregational properties of synthetic amyloid beta-peptides of Alzheimer's disease. Analysis of circular dichroism spectra. , 1992, Journal of molecular biology.

[50]  M. Stevens.  Bundle Binding in Polyelectrolyte Solutions , 1999 .

[51]  M. Stevens,et al.  Density Functional Theory of Ionic Screening: When Do Like Charges Attract? , 1990 .

[52]  H. Vinters,et al.  Deposition of monomeric, not oligomeric, Abeta mediates growth of Alzheimer's disease amyloid plaques in human brain preparations. , 1999, Biochemistry.

[53]  K. Iwata,et al.  The Alzheimer's peptide a beta adopts a collapsed coil structure in water. , 2000, Journal of structural biology.

[54]  J. Cavanagh.  Protein NMR Spectroscopy: Principles and Practice , 1995 .

[55]  G. S. Manning,et al.  Fluctuations of Counterions Condensed on Charged Polymers , 1994 .

[56]  R. Pecora.  Dynamic Light Scattering , 1985 .

[57]  D. Selkoe,et al.  Alzheimer's Disease: A Central Role for Amyloid , 1994, Journal of neuropathology and experimental neurology.