Binding Modes of Thioflavin-T to the Single-Layer β-Sheet of the Peptide Self-Assembly Mimics

Chun Wu, Matthew Biancalana, Shohei Koide, Joan Emma Shea

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

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 β-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 β-sheet (SLB) capped by two globular domains, which capture the flat, extended β-sheet features common among fibril-like surfaces. Recently, a PSAM that binds to ThT with amyloid-like affinity (low micromolar Kd) 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 β-rich structure. Here, we present molecular dynamics simulations of the binding of ThT to this PSAM β-sheet. We show that the primary binding site for ThT is along a shallow groove formed by adjacent Tyr and Leu residues on the β-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 β-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.

Original languageEnglish (US)
Pages (from-to)627-633
Number of pages7
JournalJournal of Molecular Biology
Volume394
Issue number4
DOIs
StatePublished - Dec 11 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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