Characterizing methyl-bearing side chain contacts and dynamics mediating amyloid β protofibril interactions using ¹³C(methyl)-DEST and lifetime line broadening

Angew Chem Int Ed Engl. 2014 Sep 22;53(39):10345-9. doi: 10.1002/anie.201405180. Epub 2014 Aug 11.


Many details pertaining to the formation and interactions of protein aggregates associated with neurodegenerative diseases are invisible to conventional biophysical techniques. We recently introduced (15)N dark-state exchange saturation transfer (DEST) and (15)N lifetime line-broadening to study solution backbone dynamics and position-specific binding probabilities for amyloid β (Aβ) monomers in exchange with large (2-80 MDa) protofibrillar Aβ aggregates. Here we use (13)C(methyl)DEST and lifetime line-broadening to probe the interactions and dynamics of methyl-bearing side chains in the Aβ-protofibril-bound state. We show that all methyl groups of Aβ40 populate direct-contact bound states with a very fast effective transverse relaxation rate, indicative of side-chain-mediated direct binding to the protofibril surface. The data are consistent with position-specific enhancements of (13)C(methyl)-R₂(tethered) values in tethered states, providing further insights into the structural ensemble of the protofibril-bound state.

Keywords: NMR spectroscopy; amyloid β; high-molecular-weight assemblies; protein-protein interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Carbon Isotopes / chemistry
  • Kinetics
  • Molecular Sequence Data
  • Nitrogen Isotopes / chemistry
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Interaction Domains and Motifs


  • Amyloid beta-Peptides
  • Carbon Isotopes
  • Nitrogen Isotopes