Halogenation of the N‐Terminus Tyrosine 10 Promotes Supramolecular Stabilization of the Amyloid‐β Sequence 7–12

Abstract Here, we demonstrate that introduction of halogen atoms at the tyrosine 10 phenol ring of the DSGYEV sequence derived from the flexible amyloid‐β N‐terminus, promotes its self‐assembly in the solid state. In particular, we report the crystal structures of two halogen‐modified sequences, which we found to be stabilized in the solid state by halogen‐mediated interactions. The structural study is corroborated by Non‐Covalent Interaction (NCI) analysis. Our results prove that selective halogenation of an amino acid enhances the supramolecular organization of otherwise unstructured biologically‐relevant sequences. This method may develop as a general strategy for stabilizing highly polymorphic peptide regions.

[1]  A. Genoni,et al.  NCI-ELMO: a New Method to Quickly and Accurately Detect Non-Covalent Interactions in Biosystems. , 2019, Journal of chemical theory and computation.

[2]  Orion B. Berryman,et al.  Hydrogen Bond Enhanced Halogen Bonds: A Synergistic Interaction in Chemistry and Biochemistry. , 2019, Accounts of chemical research.

[3]  D. Willbold,et al.  Solution‐Based Determination of Dissociation Constants for the Binding of Aβ42 to Antibodies , 2019, ChemistryOpen.

[4]  C. Verschoor,et al.  Atomic resolution map of the soluble amyloid beta assembly toxic surfaces† †Electronic supplementary information (ESI) available: Methods, 15N-DEST profiles, and additional statistical analyses. See DOI: 10.1039/c9sc01331h , 2019, Chemical science.

[5]  A. Redaelli,et al.  Molecular dynamics investigation of halogenated amyloidogenic peptides , 2019, Journal of Molecular Modeling.

[6]  P. Metrangolo,et al.  A halogen bond-donor amino acid for organocatalysis in water. , 2018, Chemical communications.

[7]  P. Metrangolo,et al.  Halogen bonding at the wet interfaces of an amyloid peptide structure , 2018 .

[8]  P. Metrangolo,et al.  Crystallographic insights into the self‐assembly of KLVFF amyloid‐beta peptides , 2018, Biopolymers.

[9]  G. Ullah,et al.  Origin of metastable oligomers and their effects on amyloid fibril self-assembly† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc01479e , 2018, Chemical science.

[10]  B. Ghetti,et al.  Molecular subtypes of Alzheimer’s disease , 2018, Scientific Reports.

[11]  P. Dugourd,et al.  Mass and charge distributions of amyloid fibers involved in neurodegenerative diseases: mapping heterogeneity and polymorphism† †Electronic supplementary information (ESI) available: Experimental section and supplementary figures. See DOI: 10.1039/c7sc04542e , 2018, Chemical science.

[12]  S. Chatterjee,et al.  A Small Molecule Impedes Insulin Fibrillation: Another New Role of Phenothiazine Derivatives , 2017, ChemistryOpen.

[13]  L. Hemmingsen,et al.  The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+ -Aβ Complex. , 2017, Chemistry.

[14]  F. Tagliavini,et al.  Pathogenic Aβ A2V versus protective Aβ A2T mutation: Early stage aggregation and membrane interaction. , 2017, Biophysical chemistry.

[15]  D. Kirschner,et al.  The A2V mutation as a new tool for hindering Aβ aggregation: A neutron and x-ray diffraction study , 2017, Scientific Reports.

[16]  O. Ikkala,et al.  Halogenation dictates the architecture of amyloid peptide nanostructures , 2017, Nanoscale.

[17]  T. Pillot,et al.  Structural and functional analyses of pyroglutamate-amyloid-β-specific antibodies as a basis for Alzheimer immunotherapy , 2017, The Journal of Biological Chemistry.

[18]  J. Gräfenstein,et al.  Halogen Bonding: A Powerful Tool for Modulation of Peptide Conformation , 2017, Biochemistry.

[19]  M. Erdélyi.  Application of the Halogen Bond in Protein Systems. , 2017, Biochemistry.

[20]  P. S. Ho,et al.  Structure-Energy Relationships of Halogen Bonds in Proteins. , 2017, Biochemistry.

[21]  Hailing Li,et al.  Nitration of Tyrosine Residue Y10 of Aβ1-42 Significantly Inhibits Its Aggregation and Cytotoxicity. , 2017, Chemical research in toxicology.

[22]  G. Belfort,et al.  N-Terminal Hypothesis for Alzheimer's Disease. , 2017, ACS chemical neuroscience.

[23]  G. Colombo,et al.  Crystal Structure of the DFNKF Segment of Human Calcitonin Unveils Aromatic Interactions between Phenylalanines , 2016, Chemistry.

[24]  Roland Riek,et al.  The activities of amyloids from a structural perspective , 2016, Nature.

[25]  Sara Linse,et al.  Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils. , 2016, Journal of the American Chemical Society.

[26]  Pierangelo Metrangolo,et al.  The Halogen Bond , 2016, Chemical reviews.

[27]  N. Houbenov,et al.  Supramolecular amplification of amyloid self-assembly by iodination , 2015, Nature Communications.

[28]  R. Glockshuber,et al.  Die atomare dreidimensionale Struktur von Amyloid‐β‐Fibrillen mit der Osaka‐Mutation , 2015 .

[29]  G. Sheldrick.  SHELXT – Integrated space-group and crystal-structure determination , 2015, Acta crystallographica. Section A, Foundations and advances.

[30]  G. Sheldrick.  Crystal structure refinement with SHELXL , 2015, Acta crystallographica. Section C, Structural chemistry.

[31]  R. Glockshuber,et al.  Atomic-Resolution Three-Dimensional Structure of Amyloid β Fibrils Bearing the Osaka Mutation** , 2014, Angewandte Chemie.

[32]  M. Nguyen,et al.  The Necessity of Having a Tetradentate Ligand to Extract Copper(II) Ions from Amyloids , 2014, ChemistryOpen.

[33]  G. Cavallo,et al.  Orthogonal halogen and hydrogen bonds involving a peptide bond model , 2014, CrystEngComm.

[34]  M. Heneka,et al.  Truncated and modified amyloid-beta species , 2014, Alzheimer's Research & Therapy.

[35]  C. Masters,et al.  Structural studies of the tethered N‐terminus of the Alzheimer's disease amyloid‐β peptide , 2013, Proteins.

[36]  Pavel Hobza,et al.  The relative roles of electrostatics and dispersion in the stabilization of halogen bonds. , 2013, Physical chemistry chemical physics : PCCP.

[37]  Philip R. Evans,et al.  How good are my data and what is the resolution? , 2013, Acta crystallographica. Section D, Biological crystallography.

[38]  J. Stroud.  The zipper groups of the amyloid state of proteins , 2013, Acta crystallographica. Section D, Biological crystallography.

[39]  M. Parker,et al.  Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation , 2013, Scientific Reports.

[40]  H. Vinters,et al.  Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*♦ , 2013, The Journal of Biological Chemistry.

[41]  Pavel Hobza,et al.  Strength and Character of Halogen Bonds in Protein–Ligand Complexes , 2011 .

[42]  F. Jessen,et al.  Nitration of Tyrosine 10 Critically Enhances Amyloid β Aggregation and Plaque Formation , 2011, Neuron.

[43]  Esteban Lanzarotti,et al.  Aromatic-Aromatic Interactions in Proteins: Beyond the Dimer , 2011, J. Chem. Inf. Model..

[44]  Randy J. Read,et al.  Overview of the CCP4 suite and current developments , 2011, Acta crystallographica. Section D, Biological crystallography.

[45]  Jean-Philip Piquemal,et al.  NCIPLOT: a program for plotting non-covalent interaction regions. , 2011, Journal of chemical theory and computation.

[46]  Julia Contreras-García,et al.  Revealing noncovalent interactions. , 2010, Journal of the American Chemical Society.

[47]  D. Truhlar,et al.  The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals , 2008 .

[48]  J. Danielsson,et al.  15N relaxation study of the amyloid β‐peptide: structural propensities and persistence length , 2006, Magnetic resonance in chemistry : MRC.

[49]  Eric Westhof,et al.  Halogen bonds in biological molecules. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Sheh-Yi Sheu,et al.  Energetics of hydrogen bonds in peptides , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[52]  H. Loetscher,et al.  Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. , 2012, Journal of Alzheimer's disease : JAD.

[53]  A. Barth,et al.  The infrared absorption of amino acid side chains. , 2000, Progress in biophysics and molecular biology.