Aromatic cross-strand ladders control the structure and stability of beta-rich peptide self-assembly mimics

J Mol Biol. 2008 Oct 31;383(1):205-13. doi: 10.1016/j.jmb.2008.08.031. Epub 2008 Aug 22.


Though beta-rich self-assemblies comprise a major structural class of polypeptides, a detailed understanding of the determinants of their structure and stability is lacking. In particular, the roles of repetitive stretches of side chains running the long axis of these beta-sheets, termed "cross-strand ladders," remain poorly characterized due to the inherently insoluble and heterogeneous nature of self-assemblies. To overcome these experimental challenges, we have established a complementary experimental system termed "peptide self-assembly mimics" (PSAMs). The PSAMs capture a defined number of self-assembly-like peptide repeats within a soluble beta-rich protein, making structural and energetic studies possible. In this work, we investigated the role of cross-strand ladders containing aromatic residues, which are prominent in self-assembling peptides. A combination of solution data and high-resolution crystal structures revealed that a single cross-strand ladder consisting solely of Tyr significantly stabilized, rigidified, and flattened the PSAM beta-sheet. These characteristics would stabilize each beta-sheet layer of a self-assembly and direct sheet conformations compatible with lamination. Our results therefore provide a rationale for the abundance of aromatic amino acids in fibril-forming peptides and establish important roles of cross-strand Tyr ladders in the structure and stability of beta-rich peptide self-assemblies.

Publication types

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

MeSH terms

  • Amino Acids, Aromatic / chemistry
  • Crystallography, X-Ray
  • Drug Stability
  • Models, Molecular
  • Molecular Mimicry
  • Mutation
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides / chemistry*
  • Peptides / genetics
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Thermodynamics


  • Amino Acids, Aromatic
  • Peptides

Associated data

  • PDB/2OY7
  • PDB/2OY8
  • PDB/2OYB