Self-Assembly of Flexible β-Strands into Immobile Amyloid-Like β-Sheets in Membranes As Revealed by Solid-State 19F NMR

The cationic peptide [KIGAKI](3) was designed as an amphiphilic beta-strand and serves as a model for beta-sheet aggregation in membranes. Here, we have characterized its molecular conformation, membrane alignment, and dynamic behavior using solid-state F-19 NMR. A detailed structure analysis of selectively F-19-labeled peptides was carried out in oriented DMPC bilayers. It showed a concentration-dependent transition from monomeric beta-strands to oligomeric beta-sheets. In both states, the rigid F-19-labeled side chains project straight into the lipid bilayer but they experience very different mobilities. At low peptide-to-lipid ratios <= 1:400, monomeric [KIGAKI](3) swims around freely on the membrane surface and undergoes considerable motional averaging, with essentially uncoupled phi/psi torsion angles. The flexibility of the peptide backbone in this 2D plane is reminiscent of intrinsically unstructured proteins in 3D. At high concentrations, [KIGAKI](3) self-assembles into immobilized beta-sheets, which are untwisted and lie flat on the membrane surface as amyloid-like fibrils. This is the first time the transition of monomeric beta-strands into oligomeric beta-sheets has been characterized by solid-state NMR in lipid bilayers. It promises to be a valuable approach for studying membrane-induced amyloid formation of many other, clinically relevant peptide systems.