Phase diagrams describing fibrillization by polyalanine peptides.

Amyloid fibrils are the structural components underlying the intra- and extracellular protein deposits that are associated with a variety of human diseases, including Alzheimer's, Parkinson's, and the prion diseases. In this work, we examine the thermodynamics of fibril formation using our newly-developed off-lattice intermediate-resolution protein model, PRIME. The model is simple enough to allow the treatment of large multichain systems while maintaining a fairly realistic description of protein dynamics when used in conjunction with constant-temperature discontinuous molecular dynamics, a fast alternative to conventional molecular dynamics. We conduct equilibrium simulations on systems containing 96 Ac-KA14K-NH2 peptides over a wide range of temperatures and peptide concentrations using the replica-exchange method. Based on measured values of the heat capacity, radius of gyration, and percentage of peptides that form the various structures, a phase diagram in the temperature-concentration plane is constructed delineating the regions where each structure is stable. There are four distinct single-phase regions: alpha-helices, fibrils, nonfibrillar beta-sheets, and random coils; and four two-phase regions: random coils/nonfibrillar beta-sheets, random coils/fibrils, fibrils/nonfibrillar beta-sheets, and alpha-helices/nonfibrillar beta-sheets. The alpha-helical region is at low temperature and low concentration. The nonfibrillar beta-sheet region is at intermediate temperatures and low concentrations and expands to higher temperatures as concentration is increased. The fibril region occurs at intermediate temperatures and intermediate concentrations and expands to lower as the peptide concentration is increased. The random-coil region is at high temperatures and all concentrations; this region shifts to higher temperatures as the concentration is increased.

[1]  B. Alder,et al.  Studies in Molecular Dynamics. I. General Method , 1959 .

[2]  Sue Healey,et al.  Oculopharyngeal Muscular Dystrophy , 1963, British medical journal.

[3]  D. Rapaport.  Molecular dynamics simulation of polymer chains with excluded volume , 1978 .

[4]  D. Rapaport.  Molecular dynamics study of a polymer chain in solution , 1979 .

[5]  H. C. Andersen.  Molecular dynamics simulations at constant pressure and/or temperature , 1980 .

[6]  J. Orban,et al.  Molecular dynamics of rigid and non-rigid necklaces of hard discs , 1980 .

[7]  D. Selkoe,et al.  X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. King,et al.  Deciphering the Rules of Protein Folding , 1989 .

[9]  K. Dill,et al.  Thermal stabilities of globular proteins. , 1989, Biochemistry.

[10]  S. Nosé.  Molecular Dynamics Simulations at Constant Temperature and Pressure , 1991 .

[11]  D. Brems,et al.  Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro. , 1994, Molecular pharmacology.

[12]  R. Wetzel.  Mutations and off-pathway aggregation of proteins. , 1994, Trends in biotechnology.

[13]  C. Colaco,et al.  Amyloid fibril formation , 1994, Bio/Technology.

[14]  R. Houghten,et al.  Formation of an Extremely Stable Polyalanine β-Sheet Macromolecule , 1995 .

[15]  D. Thirumalai,et al.  Kinetics and thermodynamics of folding of a de novo designed four-helix bundle protein. , 1996, Journal of molecular biology.

[16]  M. Karplus,et al.  Equilibrium thermodynamics of homopolymers and clusters: Molecular dynamics and Monte Carlo simulations of systems with square-well interactions , 1997 .

[17]  Arthur L Horwich,et al.  Deadly Conformations—Protein Misfolding in Prion Disease , 1997, Cell.

[18]  Benny D. Freeman,et al.  Molecular Dynamics for Polymeric Fluids Using Discontinuous Potentials , 1997 .

[19]  R. Houghten,et al.  Polyalanine-based peptides as models for self-associated beta-pleated-sheet complexes. , 1997, Biochemistry.

[20]  C. Blake,et al.  The structure of amyloid fibrils by electron microscopy and X-ray diffraction. , 1997, Advances in protein chemistry.

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

[22]  A. Fink.  Protein aggregation: folding aggregates, inclusion bodies and amyloid. , 1998, Folding & design.

[23]  P. Mager.  Molecular Simulation of the Amyloid β-Peptide Aβ-(1-40) of Alzheimer's Disease , 1998 .

[24]  A. Ramamoorthy,et al.  Conformational studies of human islet amyloid peptide using molecular dynamics and simulated annealing methods. , 1998, Biopolymers.

[25]  J. Kelly,et al.  The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. , 1998, Current opinion in structural biology.

[26]  F. Cohen,et al.  Thermodynamics of model prions and its implications for the problem of prion protein folding. , 1999, Journal of molecular biology.

[27]  Y. Sugita,et al.  Replica-exchange molecular dynamics method for protein folding , 1999 .

[28]  P. Mager.  Molecular Simulation of the Primary and Secondary Structures of the Aβ(1‐42)‐Peptide of Alzheimer′s Disease , 1999 .

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

[30]  D. Howlett,et al.  Computationally derived structural models of the beta-amyloid found in Alzheimer's disease plaques and the interaction with possible aggregation inhibitors. , 1999, Biopolymers.

[31]  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.

[32]  A. Irbäck,et al.  Three-helix-bundle protein in a Ramachandran model. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

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

[34]  H. Chan,et al.  Temperature dependence of hydrophobic interactions: A mean force perspective , 2000 .

[35]  R. Murphy,et al.  Effect of Ala-substitution, N- and C-terminal modification and the presence of counter ions on the structure of amyloid peptide fragment 25–35 , 2001 .

[36]  P. Mager,et al.  Molecular Simulation to Aid in the Understanding of the Aβ(1–42) Peptide of Alzheimer's Disease , 2001 .

[37]  J. Straub,et al.  Probing the origins of increased activity of the E22Q "Dutch" mutant Alzheimer's beta-amyloid peptide. , 2001, Biophysical journal.

[38]  J. Straub,et al.  Simulation study of the structure and dynamics of the Alzheimer's amyloid peptide congener in solution. , 2001, Biophysical journal.

[39]  A. V. Smith,et al.  Protein refolding versus aggregation: computer simulations on an intermediate-resolution protein model. , 2001, Journal of molecular biology.

[40]  A V Smith,et al.  Assembly of a tetrameric α‐helical bundle: Computer simulations on an intermediate‐resolution protein model , 2001, Proteins.

[41]  C. Dobson.  The structural basis of protein folding and its links with human disease. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[42]  C. Hall,et al.  α‐Helix formation: Discontinuous molecular dynamics on an intermediate‐resolution protein model , 2001, Proteins.

[43]  Long Time Dynamic Simulations: Exploring the Folding Pathways of an Alzheimer′s Amyloid Aβ‐Peptide , 2002 .

[44]  E. Žerovnik,et al.  Amyloid-fibril formation. Proposed mechanisms and relevance to conformational disease. , 2002, European journal of biochemistry.

[45]  J. W. Kelly.  Towards an understanding of amyloidogenesis , 2002, Nature Structural Biology.

[46]  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.

[47]  Ariel Fernández,et al.  Solvent environment conducive to protein aggregation , 2002, FEBS letters.

[48]  J. Straub,et al.  Long time dynamic simulations: exploring the folding pathways of an Alzheimer's amyloid Abeta-peptide. , 2002, Accounts of chemical research.

[49]  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 .

[50]  H. Stanley,et al.  Molecular dynamics simulation of the SH3 domain aggregation suggests a generic amyloidogenesis mechanism. , 2002, Journal of molecular biology.

[51]  R. Nussinov,et al.  Molecular dynamics simulations of alanine rich β‐sheet oligomers: Insight into amyloid formation , 2002, Protein science : a publication of the Protein Society.

[52]  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.

[53]  D. M. Morgan,et al.  Dynamics and fluidity of amyloid fibrils: a model of fibrous protein aggregates. , 2002, Journal of the American Chemical Society.

[54]  Ž. Eva.  Amyloid-fibril formation: Proposed mechanisms and relevance to conformational disease , 2002 .

[55]  R. Kamm,et al.  Supramolecular structure of helical ribbons self-assembled from a β-sheet peptide , 2003 .

[56]  R. Nussinov,et al.  The sequence dependence of fiber organization. A comparative molecular dynamics study of the islet amyloid polypeptide segments 22-27 and 22-29. , 2003, Journal of molecular biology.

[57]  A. Caflisch,et al.  The role of side-chain interactions in the early steps of aggregation: Molecular dynamics simulations of an amyloid-forming peptide from the yeast prion Sup35 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Francesca Massi,et al.  Structural and dynamical analysis of the hydration of the Alzheimer's β‐amyloid peptide , 2003, J. Comput. Chem..

[59]  J. Goodfellow,et al.  Simulations of human lysozyme: probing the conformations triggering amyloidosis. , 2003, Biophysical journal.

[60]  M. Lei,et al.  Why is Leu55→Pro55 transthyretin variant the most amyloidogenic: Insights from molecular dynamics simulations of transthyretin monomers , 2003, Protein science : a publication of the Protein Society.

[61]  R. Nussinov,et al.  Short peptide amyloid organization: stabilities and conformations of the islet amyloid peptide NFGAIL. , 2003, Biophysical journal.

[62]  J. Borreguero,et al.  Mechanism for the α‐helix to β‐hairpin transition , 2003, Proteins.

[63]  Yaoqi Zhou,et al.  Assembly and kinetic folding pathways of a tetrameric beta-sheet complex: molecular dynamics simulations on simplified off-lattice protein models. , 2004, Biophysical journal.

[64]  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.

[65]  Alexander J. Marchut,et al.  Solvent effects on the conformational transition of a model polyalanine peptide , 2004, Protein science : a publication of the Protein Society.

[66]  Yaoqi Zhou,et al.  Thermodynamics and stability of a β‐sheet complex: Molecular dynamics simulations on simplified off‐lattice protein models , 2004, Protein science : a publication of the Protein Society.