Multidimensional view of amyloid fibril nucleation in atomistic detail.

Starting from a disordered aggregate, we have simulated the formation of ordered amyloid-like beta structures in a system formed by 18 polyvaline chains in explicit solvent, employing molecular dynamics accelerated by bias-exchange metadynamics. We exploited 8 different collective variables to compute the free energy of hundreds of putative aggregate structures, with variable content of parallel and antiparallel β-sheets and different packing among the sheets. This allowed characterizing in detail a possible nucleation pathway for the formation of amyloid fibrils: first the system forms a relatively large ordered nucleus of antiparallel β-sheets, and then a few parallel sheets start appearing. The relevant nucleation process culminates at this point: when a sufficient number of parallel sheets is formed, the free energy starts to decrease toward a new minimum in which this structure is predominant. The complex nucleation pathway we found cannot be described within classical nucleation theory, namely employing a unique simple reaction coordinate like the total content of β-sheets.

[1]  Berk Hess,et al.  LINCS: A linear constraint solver for molecular simulations , 1997 .

[2]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[3]  Berg,et al.  Multicanonical ensemble: A new approach to simulate first-order phase transitions. , 1992, Physical review letters.

[4]  G. Hummer,et al.  Optimized molecular dynamics force fields applied to the helix-coil transition of polypeptides. , 2009, The journal of physical chemistry. B.

[5]  D. Eisenberg,et al.  Characteristics of amyloid-related oligomers revealed by crystal structures of macrocyclic β-sheet mimics. , 2011, Journal of the American Chemical Society.

[6]  Sampling the self-assembly pathways of KFFE hexamers. , 2004, Biophysical journal.

[7]  P. Kollman,et al.  How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? , 2000 .

[8]  C. Branden,et al.  Introduction to protein structure , 1991 .

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

[10]  Jiyong Park,et al.  Thermodynamic Selection of Steric Zipper Patterns in the Amyloid Cross-β Spine , 2009, PLoS Comput. Biol..

[11]  Da-Wei Li,et al.  Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment , 2008, PLoS Comput. Biol..

[12]  Alessandro Laio,et al.  METAGUI. A VMD interface for analyzing metadynamics and molecular dynamics simulations , 2012, Comput. Phys. Commun..

[13]  J. Straub,et al.  Dry amyloid fibril assembly in a yeast prion peptide is mediated by long-lived structures containing water wires , 2010, Proceedings of the National Academy of Sciences.

[14]  R. Lerner,et al.  Oxidative metabolites accelerate Alzheimer's amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation. , 2005, Biochemistry.

[15]  Michele Vendruscolo,et al.  Characterization of the nucleation barriers for protein aggregation and amyloid formation , 2007, HFSP journal.

[16]  M. Parrinello,et al.  Polymorphic transitions in single crystals: A new molecular dynamics method , 1981 .

[17]  G. Favrin,et al.  Oligomerization of amyloid Abeta16-22 peptides using hydrogen bonds and hydrophobicity forces. , 2004, Biophysical journal.

[18]  Hoover,et al.  Canonical dynamics: Equilibrium phase-space distributions. , 1985, Physical review. A, General physics.

[19]  Vijay S Pande,et al.  Simulating oligomerization at experimental concentrations and long timescales: A Markov state model approach. , 2008, The Journal of chemical physics.

[20]  Normand Mousseau,et al.  A Multiscale Approach to Characterize the Early Aggregation Steps of the Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35 , 2011, PLoS Comput. Biol..

[21]  A. Laio,et al.  Escaping free-energy minima , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[23]  Amedeo Caflisch,et al.  Interpreting the aggregation kinetics of amyloid peptides. , 2006, Journal of molecular biology.

[24]  A. Laio,et al.  Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science , 2008 .

[25]  C. Mousseau.  Exploring the Early Steps of Amyloid Peptide Aggregation by , 2005 .

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

[27]  Guanghong Wei,et al.  Self-assembly of amyloid-forming peptides by molecular dynamics simulations. , 2008, Frontiers in bioscience : a journal and virtual library.

[28]  C. Dobson,et al.  Protein misfolding, functional amyloid, and human disease. , 2006, Annual review of biochemistry.

[29]  A. Irbäck,et al.  Spontaneous β‐barrel formation: An all‐atom Monte Carlo study of Aβ16–22 oligomerization , 2008 .

[30]  Robert A. Grothe,et al.  Structure of the cross-β spine of amyloid-like fibrils , 2005, Nature.

[31]  David Chandler,et al.  Transition path sampling: throwing ropes over rough mountain passes, in the dark. , 2002, Annual review of physical chemistry.

[32]  Silvio C. E. Tosatto,et al.  The PASTA server for protein aggregation prediction. , 2007, Protein engineering, design & selection : PEDS.

[33]  Heather T. McFarlane,et al.  Atomic structures of amyloid cross-β spines reveal varied steric zippers , 2007, Nature.

[34]  Michele Vendruscolo,et al.  Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils , 2007, PLoS Comput. Biol..

[35]  P. Derreumaux.  From polypeptide sequences to structures using Monte Carlo simulations and an optimized potential , 1999 .

[36]  Christopher M Dobson,et al.  The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation , 2002, The EMBO journal.

[37]  Carol K Hall,et al.  Spontaneous fibril formation by polyalanines; discontinuous molecular dynamics simulations. , 2006, Journal of the American Chemical Society.

[38]  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.

[39]  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.

[40]  M Karplus,et al.  The fundamentals of protein folding: bringing together theory and experiment. , 1999, Current opinion in structural biology.

[41]  Ruth Nussinov,et al.  Simulations as analytical tools to understand protein aggregation and predict amyloid conformation. , 2006, Current opinion in chemical biology.

[42]  A. Laio,et al.  Optimizing the performance of bias-exchange metadynamics: folding a 48-residue LysM domain using a coarse-grained model. , 2010, The journal of physical chemistry. B.

[43]  Massimiliano Bonomi,et al.  PLUMED: A portable plugin for free-energy calculations with molecular dynamics , 2009, Comput. Phys. Commun..

[44]  D Thirumalai,et al.  Monomer adds to preformed structured oligomers of Aβ-peptides by a two-stage dock–lock mechanism , 2007, Proceedings of the National Academy of Sciences.

[45]  S. Lindquist,et al.  Structural insights into a yeast prion illuminate nucleation and strain diversity , 2005, Nature.

[46]  D. Teplow,et al.  Quasielastic light scattering for protein assembly studies. , 2005, Methods in molecular biology.

[47]  S. Nosé.  A molecular dynamics method for simulations in the canonical ensemble , 1984 .

[48]  Dominic M. Walsh,et al.  Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons , 1999, The Journal of Neuroscience.

[49]  S. Lindquist,et al.  Nucleated conformational conversion and the replication of conformational information by a prion determinant. , 2000, Science.

[50]  A. Laio,et al.  A bias-exchange approach to protein folding. , 2007, The journal of physical chemistry. B.

[51]  Normand Mousseau,et al.  Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent , 2009, Proteins.

[52]  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.

[53]  D. Teplow,et al.  Quasielastic Light Scattering Study of Amyloid β-Protein Fibril Formation , 2006 .

[54]  L. Serpell,et al.  Common core structure of amyloid fibrils by synchrotron X-ray diffraction. , 1997, Journal of molecular biology.

[55]  Satoshi Takahashi,et al.  Direct Observation of Aβ Amyloid Fibril Growth and Inhibition , 2004 .

[56]  J. Sipe,et al.  Review: history of the amyloid fibril. , 2000, Journal of structural biology.

[57]  R. Swendsen,et al.  THE weighted histogram analysis method for free‐energy calculations on biomolecules. I. The method , 1992 .

[58]  P. Derreumaux,et al.  Low molecular weight oligomers of amyloid peptides display beta-barrel conformations: a replica exchange molecular dynamics study in explicit solvent. , 2010, The Journal of chemical physics.

[59]  Joan-Emma Shea,et al.  Effect of beta-sheet propensity on peptide aggregation. , 2009, The Journal of chemical physics.

[60]  Alessandro Laio,et al.  Protein Folding and Ligand-Enzyme Binding from Bias-Exchange Metadynamics Simulations , 2012 .

[61]  Alessandro Laio,et al.  A Collective Variable for the Efficient Exploration of Protein Beta-Sheet Structures: Application to SH3 and GB1. , 2009, Journal of chemical theory and computation.

[62]  Generating ensemble averages for small proteins from extended conformations by Monte Carlo simulations. , 2000, Physical review letters.

[63]  Alessandro Laio,et al.  A Kinetic Model of Trp-Cage Folding from Multiple Biased Molecular Dynamics Simulations , 2009, PLoS Comput. Biol..

[64]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

[65]  C. Dobson,et al.  Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases , 2002, Nature.