Binding modes of thioflavin-T to the single-layer beta-sheet of the peptide self-assembly mimics

J Mol Biol. 2009 Dec 11;394(4):627-33. doi: 10.1016/j.jmb.2009.09.056. Epub 2009 Sep 30.


Although the amyloid dye thioflavin-T (ThT) is among the most widely used tools in the study of amyloid fibrils, the mechanism by which ThT binds to fibrils and other beta-rich peptide self-assemblies remains elusive. The development of the water-soluble peptide self-assembly mimic (PSAM) system has provided a set of ideal model proteins for experimentally exploring the properties and minimal dye-binding requirements of amyloid fibrils. PSAMs consist of a single-layer beta-sheet (SLB) capped by two globular domains, which capture the flat, extended beta-sheet features common among fibril-like surfaces. Recently, a PSAM that binds to ThT with amyloid-like affinity (low micromolar K(d)) has been designed, and its crystal structure in the absence of bound ThT was determined. This PSAM thus provides a unique opportunity to examine the interactions of ThT with a beta-rich structure. Here, we present molecular dynamics simulations of the binding of ThT to this PSAM beta-sheet. We show that the primary binding site for ThT is along a shallow groove formed by adjacent Tyr and Leu residues on the beta-sheet surface. These simulations provide an atomic-scale rationale for this PSAM's experimentally determined dye-binding properties. Together, our results suggest that an aromatic-hydrophobic groove spanning across four consecutive beta-strands represents a minimal ThT binding site on amyloid fibrils. Grooves formed by aromatic-hydrophobic residues on amyloid fibril surfaces may therefore offer a generic mode of recognition for amyloid dyes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Benzothiazoles
  • Binding Sites
  • Kinetics
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Secondary
  • Thiazoles / metabolism*


  • Amyloid beta-Peptides
  • Benzothiazoles
  • Thiazoles
  • thioflavin T