En route to an amyloid fibril

Among the villains in human diseases are amyloid fibrils, long and tough structures that self-assemble from misfolded proteins (see Physics Today, June 2013, page 16 ). Unraveling the actual assembly process is becoming increasingly important as research shows that some so-called intermediates—small structures that arise and then vanish during the assembly—have a large impact on the ensuing disease. But the transience of those intermediates makes them difficult to study. A team led by Martin Zanni of the University of Wisconsin has now used rapid-scan two-dimensional IR spectroscopy to watch amylin peptides as they aggregate into fibrils that are implicated in type-2 diabetes. (For more on multidimensional spectroscopy, see the article by Steven Cundiff and Shaul Mukamel, Physics Today, July 2013, page 44 .) One element of all fibrils is the β sheet, an adjacent stacking of short strings of peptides known as β strands. The researchers found that a specific portion of the peptide forms a temporary parallel β-sheet structure before breaking into the disordered loop of the fiber. The team confirmed the presence of that intermediate with other experiments and with molecular dynamics simulations. The observation helps explain the previously known importance of that particular sequence in the peptide to diabetes development. It also explains the so-called lag phase, when toxic intermediates are present prior to fibril assembly: The intermediates seem to form a free-energy barrier that the reactants must then surmount in order to proceed with forming a fibril. (L. E. Buchanan et al., Proc. Nat. Acad. Sci. USA 110, 19285, 2013, doi:10.1073/pnas.1314481110 .)