Structure and Dynamics of Parallel β-Sheets, Hydrophobic Core, and Loops in Alzheimer's Aβ Fibrils

We explore the relative contributions of different structural elements to the stability of Aβ fibrils by molecular-dynamics simulations performed over a broad range of temperatures (298 K to 398 K). Our fibril structures are based on solid-state nuclear magnetic resonance experiments of Aβ(1–40) peptides, with sheets of parallel β-strands connected by loops and stabilized by interior salt bridges. We consider models with different interpeptide interfaces, and different staggering of the N- and C-terminal β-strands along the fibril axis. Multiple 10–20 ns molecular-dynamics simulations show that fibril segments with 12 peptides are stable at ambient temperature. The different models converge toward an interdigitated side-chain packing, and present water channels solvating the interior D23/K28 salt bridges. At elevated temperatures, we observe the early phases of fibril dissociation as a loss of order in the hydrophilic loops connecting the two β-strands, and in the solvent-exposed N-terminal β-sheets. As the most dramatic structural change, we observe collective sliding of the N- and C-terminal β-sheets on top of each other. The interior C-terminal β-sheets in the hydrophobic core remain largely intact, indicating that their formation and stability is crucial to the dissociation/elongation and stability of Aβ fibrils.

[1]  T. Darden,et al.  An Atomic Model for the Pleated β-Sheet Structure of Aβ Amyloid Protofilaments , 1999 .

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

[3]  D. Thirumalai,et al.  Dissecting the assembly of A β 16-22 amyloid peptides into antiparallel β-sheets , 2002 .

[4]  R. Nussinov,et al.  Insights into amyloid structural formation and assembly through computational approaches , 2004, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[5]  P. Lansbury,et al.  Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. , 2003, Annual review of neuroscience.

[6]  R. Tycko,et al.  Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils. , 2006, Biochemistry.

[7]  Ruth Nussinov,et al.  Atomic-Level Description of Amyloid β-Dimer Formation , 2006 .

[8]  Gerhard Hummer,et al.  Molecular dynamics simulations of Alzheimer's β-amyloid protofilaments , 2005 .

[9]  C. Chothia,et al.  Orthogonal packing of beta-pleated sheets in proteins. , 1982, Biochemistry.

[10]  C. Hall,et al.  Molecular dynamics simulations of spontaneous fibril formation by random-coil peptides. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Nussinov,et al.  Stabilities and conformations of Alzheimer's β-amyloid peptide oligomers (Aβ16–22, Aβ16–35, and Aβ10–35): Sequence effects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[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]  R. Nussinov,et al.  The stability of monomeric intermediates controls amyloid formation: Abeta25-35 and its N27Q mutant. , 2006, Biophysical journal.

[14]  B. Brooks,et al.  Constant pressure molecular dynamics simulation: The Langevin piston method , 1995 .

[15]  H. Jaeger,et al.  Conducting nanowires built by controlled self-assembly of amyloid fibers and selective metal deposition , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Richard D. Leapman,et al.  Self-Propagating, Molecular-Level Polymorphism in Alzheimer's ß-Amyloid Fibrils , 2005, Science.

[17]  Christopher M. Dobson,et al.  Molecular recycling within amyloid fibrils , 2005, Nature.

[18]  Christopher M Dobson,et al.  Probing the pressure-temperature stability of amyloid fibrils provides new insights into their molecular properties. , 2006, Biochimica et biophysica acta.

[19]  D. Thirumalai,et al.  Exploring protein aggregation and self‐propagation using lattice models: Phase diagram and kinetics , 2002, Protein science : a publication of the Protein Society.

[20]  D. Thirumalai,et al.  Proteins associated with diseases show enhanced sequence correlation between charged residues , 2004, Bioinform..

[21]  Michele Vendruscolo,et al.  Theoretical approaches to protein aggregation. , 2006, Protein and peptide letters.

[22]  P. Argos,et al.  Knowledge‐based protein secondary structure assignment , 1995, Proteins.

[23]  A Caflisch,et al.  A molecular dynamics approach to the structural characterization of amyloid aggregation. , 2006, Journal of molecular biology.

[24]  D Thirumalai,et al.  Probing the initial stage of aggregation of the Abeta(10-35)-protein: assessing the propensity for peptide dimerization. , 2005, Journal of molecular biology.

[25]  H. Stanley,et al.  Folding events in the 21-30 region of amyloid β-protein (Aβ) studied in silico , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  R. Tycko,et al.  Abeta40-Lactam(D23/K28) models a conformation highly favorable for nucleation of amyloid. , 2005, Biochemistry.

[27]  D. Thirumalai,et al.  Emerging ideas on the molecular basis of protein and peptide aggregation. , 2003, Current opinion in structural biology.

[28]  Alessandro Laio,et al.  Stability and structure of oligomers of the Alzheimer peptide Abeta16-22: from the dimer to the 32-mer. , 2006, Biophysical journal.

[29]  P. Lansbury,et al.  Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores. , 2003, Journal of molecular biology.

[30]  J. D. Figueroa-Villar,et al.  Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Aβ oligomerization , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[32]  N. Arispe.  Architecture of the Alzheimer’s AβP Ion Channel Pore , 2003, The Journal of Membrane Biology.

[33]  Hai Lin,et al.  Amyloid ion channels: a common structural link for protein-misfolding disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Eng-Hui Yap,et al.  Determining the critical nucleus and mechanism of fibril elongation of the Alzheimer's Abeta(1-40) peptide. , 2007, Journal of molecular biology.

[35]  R. Leapman,et al.  A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Roger D Kamm,et al.  Kinetic control of dimer structure formation in amyloid fibrillogenesis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[37]  D. Selkoe,et al.  Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease. , 1994, Annual review of cell biology.

[38]  Laxmikant V. Kale,et al.  NAMD2: Greater Scalability for Parallel Molecular Dynamics , 1999 .

[39]  J. Straub,et al.  Charge states rather than propensity for β‐structure determine enhanced fibrillogenesis in wild‐type Alzheimer's β‐amyloid peptide compared to E22Q Dutch mutant , 2002 .

[40]  D. Gordon,et al.  Probing the role of backbone hydrogen bonding in beta-amyloid fibrils with inhibitor peptides containing ester bonds at alternate positions. , 2003, Biochemistry.

[41]  M. Kirkitadze,et al.  Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. , 2001, Journal of molecular biology.

[42]  R. Tycko.  Progress towards a molecular-level structural understanding of amyloid fibrils. , 2004, Current opinion in structural biology.

[43]  D. Teplow,et al.  On the nucleation of amyloid β‐protein monomer folding , 2005 .

[44]  H. Stanley,et al.  Molecular Dynamics Simulation of Amyloid β Dimer Formation , 2004, physics/0403040.

[45]  Scott Brown,et al.  Influence of denatured and intermediate states of folding on protein aggregation , 2005, Protein science : a publication of the Protein Society.

[46]  S. Constantinescu,et al.  Inhibitors of amyloid toxicity based on beta-sheet packing of Abeta40 and Abeta42. , 2006, Biochemistry.

[47]  J. Wands,et al.  Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[48]  C. Blake,et al.  From the globular to the fibrous state: protein structure and structural conversion in amyloid formation , 1998, Quarterly Reviews of Biophysics.

[49]  A. Li,et al.  Identification and characterization of the unfolding transition state of chymotrypsin inhibitor 2 by molecular dynamics simulations. , 1996, Journal of molecular biology.

[50]  C. Barrow,et al.  Surface behavior and lipid interaction of Alzheimer beta-amyloid peptide 1-42: a membrane-disrupting peptide. , 2005, Biophysical journal.

[51]  M. Klein,et al.  Constant pressure molecular dynamics algorithms , 1994 .

[52]  Yuji Goto,et al.  Kinetically controlled thermal response of beta2-microglobulin amyloid fibrils. , 2005, Journal of Molecular Biology.

[53]  H. Shao,et al.  Solution structures of micelle-bound amyloid beta-(1-40) and beta-(1-42) peptides of Alzheimer's disease. , 1999, Journal of molecular biology.

[54]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[55]  H. Stanley,et al.  Solvent and mutation effects on the nucleation of amyloid beta-protein folding. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[56]  R. Tycko,et al.  Polymorphic fibril formation by residues 10-40 of the Alzheimer's beta-amyloid peptide. , 2006, Biophysical journal.

[57]  Andrij Baumketner,et al.  Structure of the 21–30 fragment of amyloid β‐protein , 2006 .

[58]  E. Gazit,et al.  Molecular Self-Assembly of Peptide Nanostructures: Mechanism of Association and Potential Uses , 2006 .

[59]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .