The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth

Many proteins have the potential to aggregate into amyloid fibrils, protein polymers associated with a wide range of human disorders such as Alzheimer’s and Parkinson’s disease. The thermodynamic stability of amyloid fibrils, in contrast to that of folded proteins, is not well understood: the balance between entropic and enthalpic terms, including the chain entropy and the hydrophobic effect, are poorly characterised. Using a combination of theory, in vitro experiments, simulations of a coarse-grained protein model and meta-data analysis, we delineate the enthalpic and entropic contributions that dominate amyloid fibril elongation. Our prediction of a characteristic temperature-dependent enthalpic signature is confirmed by the performed calorimetric experiments and a meta-analysis over published data. From these results we are able to define the necessary conditions to observe cold denaturation of amyloid fibrils. Overall, we show that amyloid fibril elongation is associated with a negative heat capacity, the magnitude of which correlates closely with the hydrophobic surface area that is buried upon fibril formation, highlighting the importance of hydrophobicity for fibril stability.

[1]  Andrey V. Kustov,et al.  Amino acid behavior in aqueous amide solutions: Temperature dependence of the l-phenylalanine–N,N-dimethylformamide interaction , 2013 .

[2]  W. J. Fokkink,et al.  The characteristics of molten globule states and folding pathways strongly depend on the sequence of a protein , 2018, Molecular Physics.

[3]  Mireille Dumoulin,et al.  Identification of the core structure of lysozyme amyloid fibrils by proteolysis. , 2006, Journal of molecular biology.

[4]  Sanne Abeln,et al.  A Simple Lattice Model That Captures Protein Folding, Aggregation and Amyloid Formation , 2014, PloS one.

[5]  Sanne Abeln,et al.  Interplay between folding and assembly of fibril-forming polypeptides. , 2013, Physical review letters.

[6]  Peter Westh,et al.  The role of protonation in protein fibrillation , 2010, FEBS letters.

[7]  P. Privalov,et al.  Energetics of interactions of aromatic hydrocarbons with water. , 1994, Biophysical chemistry.

[8]  Christian Leisner,et al.  Raft lipids as common components of human extracellular amyloid fibrils. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Philippe Derreumaux,et al.  Lattice model for amyloid peptides: OPEP force field parametrization and applications to the nucleus size of Alzheimer's peptides. , 2016, The Journal of chemical physics.

[10]  D. Chandler.  Interfaces and the driving force of hydrophobic assembly , 2005, Nature.

[11]  Sanne Abeln,et al.  Consistent Treatment of Hydrophobicity in Protein Lattice Models Accounts for Cold Denaturation. , 2015, Physical review letters.

[12]  Yuji Goto,et al.  Direct Measurement of the Thermodynamic Parameters of Amyloid Formation by Isothermal Titration Calorimetry* , 2004, Journal of Biological Chemistry.

[13]  R. L. Baldwin.  Energetics of protein folding. , 2007, Journal of molecular biology.

[14]  L Liu,et al.  A study on the enthalpy-entropy compensation in protein unfolding. , 2000, Biophysical chemistry.

[15]  Vinod Subramaniam,et al.  Distinct Mechanisms Determine α-Synuclein Fibril Morphology during Growth and Maturation. , 2017, ACS chemical neuroscience.

[16]  Sara Linse,et al.  Surface effects on aggregation kinetics of amyloidogenic peptides. , 2014, Journal of the American Chemical Society.

[17]  Gerald McDonnell,et al.  The challenge of prion decontamination. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

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

[19]  Marie Doumic,et al.  Insights into the variability of nucleated amyloid polymerization by a minimalistic model of stochastic protein assembly. , 2015, The Journal of chemical physics.

[20]  J H Lakey,et al.  Heat does not come in different colours: entropy-enthalpy compensation, free energy windows, quantum confinement, pressure perturbation calorimetry, solvation and the multiple causes of heat capacity effects in biomolecular interactions. , 2001, Biophysical chemistry.

[21]  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.

[22]  Ronald Wetzel,et al.  Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions , 2006, Proceedings of the National Academy of Sciences.

[23]  Kenichiro Koga,et al.  The hydrophobic effect , 2003 .

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

[25]  Kazumasa Sakurai,et al.  Conformational stability of amyloid fibrils of β2‐microglobulin probed by guanidine‐hydrochloride‐induced unfolding , 2004, FEBS letters.

[26]  K. Dill,et al.  Protein folding in the landscape perspective: Chevron plots and non‐arrhenius kinetics , 1998, Proteins.

[27]  Dietmar Riedel,et al.  Dissociation of amyloid fibrils of alpha-synuclein in supercooled water. , 2008, Angewandte Chemie.

[28]  Michele Vendruscolo,et al.  Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation , 2014, Proceedings of the National Academy of Sciences.

[29]  Sheena E. Radford,et al.  The structure of a beta2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism. , 2018 .

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

[31]  Daan Frenkel,et al.  Designing specificity of protein-substrate interactions. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[32]  Christoph Dellago,et al.  Role of Water in the Selection of Stable Proteins at Ambient and Extreme Thermodynamic Conditions , 2017 .

[33]  Joan-Emma Shea,et al.  Computational studies of protein aggregation: methods and applications. , 2015, Annual review of physical chemistry.

[34]  Sheena E. Radford,et al.  β2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH , 2014, PloS one.

[35]  Zhaoqian Su,et al.  Thermodynamic Stability of Polar and Nonpolar Amyloid Fibrils. , 2019, Journal of chemical theory and computation.

[36]  Alexander K. Buell,et al.  Detailed analysis of the energy barriers for amyloid fibril growth. , 2012, Angewandte Chemie.

[37]  F. H. White,et al.  Lysozyme and alpha-lactalbumin: structure, function, and interrelationships. , 1991, Advances in protein chemistry.

[38]  Robert G Griffin,et al.  The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism , 2018, Nature Communications.

[39]  Daniel Erik Otzen,et al.  Glucagon fibril polymorphism reflects differences in protofilament backbone structure. , 2010, Journal of molecular biology.

[40]  Nicola Vettore,et al.  Thermodynamics of amyloid fibril formation from chemical depolymerization. , 2019, Physical chemistry chemical physics : PCCP.

[41]  Charles D. Schwieters,et al.  Solid-State NMR Structure of a Pathogenic Fibril of Full-Length Human α-Synuclein , 2016, Nature Structural &Molecular Biology.

[42]  Michele Vendruscolo,et al.  Metastability of native proteins and the phenomenon of amyloid formation. , 2011, Journal of the American Chemical Society.

[43]  Peter G Bolhuis,et al.  Primary Fibril Nucleation of Aggregation Prone Tau Fragments PHF6 and PHF6. , 2017, The journal of physical chemistry. B.

[44]  E. Shakhnovich,et al.  Engineering of stable and fast-folding sequences of model proteins. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[45]  George M. Whitesides,et al.  Why Are Proteins Charged? Networks of Charge—Charge Interactions in Proteins Measured by Charge Ladders and Capillary Electrophoresis , 2006 .

[46]  Christopher M Dobson,et al.  Surface attachment of protein fibrils via covalent modification strategies. , 2010, The journal of physical chemistry. B.

[47]  Erik van Dijk,et al.  The Hydrophobic Temperature Dependence of Amino Acids Directly Calculated from Protein Structures , 2015, PLoS Comput. Biol..

[48]  Ilpo Vattulainen,et al.  The hydrophobic effect and its role in cold denaturation. , 2010, Cryobiology.

[49]  Peter G Wolynes,et al.  Water Mediated Interactions and the Protein Folding Phase Diagram in the Temperature-Pressure Plane. , 2015, The journal of physical chemistry. B.

[50]  P G Bolhuis,et al.  Dynamics of Hydration Water around Native and Misfolded α-Lactalbumin. , 2016, The journal of physical chemistry. B.

[51]  Peter Tompa,et al.  AmyPro: a database of proteins with validated amyloidogenic regions , 2017, Nucleic Acids Res..

[52]  Phillip L Geissler,et al.  Dynamics of Seeded Aβ40-Fibril Growth from Atomistic Molecular Dynamics Simulations: Kinetic Trapping and Reduced Water Mobility in the Locking Step. , 2016, Journal of the American Chemical Society.

[53]  Alexander K. Buell,et al.  Thermodynamics of Polypeptide Supramolecular Assembly in the Short-Chain Limit. , 2017, Journal of the American Chemical Society.

[54]  Hue Sun Chan,et al.  Simple two‐state protein folding kinetics requires near‐levinthal thermodynamic cooperativity , 2003, Proteins.

[55]  Young-Ho Lee,et al.  Cold denaturation of α-synuclein amyloid fibrils. , 2014, Angewandte Chemie.

[56]  Pietro Cicuta,et al.  Interaction with prefibrillar species and amyloid-like fibrils changes the stiffness of lipid bilayers. , 2017, Physical chemistry chemical physics : PCCP.

[57]  E. Shakhnovich,et al.  A new approach to the design of stable proteins. , 1993, Protein engineering.

[58]  S. Grzesiek,et al.  High-pressure NMR reveals close similarity between cold and alcohol protein denaturation in ubiquitin , 2013, Proceedings of the National Academy of Sciences.

[59]  Hue Sun Chan,et al.  Desolvation is a likely origin of robust enthalpic barriers to protein folding. , 2005, Journal of molecular biology.

[60]  Sanne Abeln,et al.  Competition between surface adsorption and folding of fibril-forming polypeptides. , 2015, Physical review. E, Statistical, nonlinear, and soft matter physics.

[61]  Flavio Seno,et al.  Insight into the Structure of Amyloid Fibrils from the Analysis of Globular Proteins , 2006, PLoS Comput. Biol..

[62]  Jesper Søndergaard Pedersen,et al.  The changing face of glucagon fibrillation: structural polymorphism and conformational imprinting. , 2006, Journal of molecular biology.

[63]  Dietmar Riedel,et al.  Titelbild: Dissociation of Amyloid Fibrils of α‐Synuclein in Supercooled Water (Angew. Chem. 27/2008) , 2008 .

[64]  H. Scheraga,et al.  Role of interchain interactions in the stabilization of the right-handed twist of beta-sheets. , 1983, Journal of molecular biology.

[65]  M. Karplus,et al.  Kinetics of protein folding. A lattice model study of the requirements for folding to the native state. , 1994, Journal of molecular biology.

[66]  Pieter Rein ten Wolde,et al.  Drying-induced hydrophobic polymer collapse , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Marianne Rooman,et al.  Physical and molecular bases of protein thermal stability and cold adaptation. , 2017, Current opinion in structural biology.

[68]  E. Shakhnovich,et al.  Proteins with selected sequences fold into unique native conformation. , 1994, Physical review letters.

[69]  Peter Güntert,et al.  Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril , 2016, Proceedings of the National Academy of Sciences.

[70]  D Frenkel,et al.  Designing refoldable model molecules. , 2003, Physical review. E, Statistical, nonlinear, and soft matter physics.

[71]  Alexander K. Buell,et al.  Physical determinants of the self-replication of protein fibrils , 2016, Nature Physics.

[72]  Sanne Abeln,et al.  Accounting for protein-solvent contacts facilitates design of nonaggregating lattice proteins. , 2011, Biophysical journal.

[73]  Christopher M Dobson,et al.  Perturbation of the stability of amyloid fibrils through alteration of electrostatic interactions. , 2011, Biophysical journal.

[74]  Daan Frenkel,et al.  Monte Carlo study of substrate-induced folding and refolding of lattice proteins. , 2007, Biophysical journal.

[75]  Alexander K. Buell,et al.  The growth of amyloid fibrils: rates and mechanisms. , 2019, Biochemical Journal.

[76]  Simone Melchionna,et al.  Coarse‐grained and All‐atom Simulations towards the Early and Late Steps of Amyloid Fibril Formation , 2017 .

[77]  Bertrand Morel,et al.  The thermodynamic stability of amyloid fibrils studied by differential scanning calorimetry. , 2010, The journal of physical chemistry. B.

[78]  D Chandler,et al.  Temperature and length scale dependence of hydrophobic effects and their possible implications for protein folding. , 2000, Proceedings of the National Academy of Sciences of the United States of America.