High-resolution structure of a self-assembly-competent form of a hydrophobic peptide captured in a soluble beta-sheet scaffold

J Mol Biol. 2008 Apr 25;378(2):459-67. doi: 10.1016/j.jmb.2008.02.051. Epub 2008 Mar 4.


beta-Rich self-assembly is a major structural class of polypeptides, but still little is known about its atomic structures and biophysical properties. Major impediments for structural and biophysical studies of peptide self-assemblies include their insolubility and heterogeneous composition. We have developed a model system, termed peptide self-assembly mimic (PSAM), based on the single-layer beta-sheet of Borrelia outer surface protein A. PSAM allows for the capture of a defined number of self-assembly-like peptide repeats within a water-soluble protein, making structural and energetic studies possible. In this work, we extend our PSAM approach to a highly hydrophobic peptide sequence. We show that a penta-Ile peptide (Ile(5)), which is insoluble and forms beta-rich self-assemblies in aqueous solution, can be captured within the PSAM scaffold in a form capable of self-assembly. The 1.1-A crystal structure revealed that the Ile(5) stretch forms a highly regular beta-strand within this flat beta-sheet. Self-assembly models built with multiple copies of the crystal structure of the Ile(5) peptide segment showed no steric conflict, indicating that this conformation represents an assembly-competent form. The PSAM retained high conformational stability, suggesting that the flat beta-strand of the Ile(5) stretch primed for self-assembly is a low-energy conformation of the Ile(5) stretch and rationalizing its high propensity for self-assembly. The ability of the PSAM to "solubilize" an otherwise insoluble peptide stretch suggests the potential of the PSAM approach to the characterization of self-assembling peptides.

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

  • Antigens, Surface / chemistry*
  • Bacterial Outer Membrane Proteins / chemistry*
  • Bacterial Vaccines / chemistry*
  • Borrelia
  • Circular Dichroism
  • Crystallography, X-Ray
  • Hydrophobic and Hydrophilic Interactions
  • Isoleucine / chemistry*
  • Lipoproteins / chemistry*
  • Methods
  • Microscopy, Atomic Force
  • Models, Molecular
  • Oligopeptides / chemistry*
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Secondary


  • Antigens, Surface
  • Bacterial Outer Membrane Proteins
  • Bacterial Vaccines
  • Lipoproteins
  • Oligopeptides
  • OspA protein
  • Isoleucine