10.1021/bi036248t.s001 Waltteri Hosia Waltteri Hosia Niklas Bark Niklas Bark Edvards Liepinsh Edvards Liepinsh Agneta Tjernberg Agneta Tjernberg Bengt Persson Bengt Persson Dan Hallén Dan Hallén Johan Thyberg Johan Thyberg Jan Johansson Jan Johansson Lars Tjernberg Lars Tjernberg Folding into a β-Hairpin Can Prevent Amyloid Fibril Formation<sup>†</sup> American Chemical Society 2004 size exclusion chromatography motif form fibrils sequence electrospray mass spectrometry polymerization dodecapeptide KFFEYNGKKFFE modeling studies fibril formation tetrapeptide KFFE KFFE tetrapeptides NMR spectroscopy amyloidogenic properties dodecapeptide KFFEAAAKKFFE forms fibril bundles sedimentation analysis 2004-04-27 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Folding_into_a_Hairpin_Can_Prevent_Amyloid_Fibril_Formation_sup_sup_/3341671 The tetrapeptide KFFE is one of the shortest amyloid fibril-forming peptides described. Herein, we have investigated how the structural environment of this motif affects polymerization. Using a turn motif (YNGK) or a less rigid sequence (AAAK) to fuse two KFFE tetrapeptides, we show by several biophysical methods that the amyloidogenic properties are strongly dependent on the structural environment. The dodecapeptide KFFEAAAKKFFE forms abundant thick fibril bundles. Freshly dissolved KFFEAAAKKFFE is monomeric and shows mainly disordered secondary structure, as evidenced by circular dichroism, NMR spectroscopy, hydrogen/deuterium exchange measurements, and molecular modeling studies. In sharp contrast, the dodecapeptide KFFEYNGKKFFE does not form fibrils but folds into a stable β-hairpin. This structure can oligomerize into a stable 12-mer and multiples thereof, as shown by size exclusion chromatography, sedimentation analysis, and electrospray mass spectrometry. These data indicate that the structural context in which a potential fibril forming sequence is present can prevent fibril formation by favoring self-limiting oligomerization over polymerization.