Photo-initiated Disassembly of Fibrils: Application to Amyloids and Hydrogels

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): Protein self-assembly, the spontaneous organization of monomers into highly ordered structures, has become a significant aspect of biological research. A large portion is dedicated to understanding the self-assembly of insoluble amyloid deposits from misfolded proteins, which has been linked to incurable diseases, such as Alzheimer's, Parkinson's, and Type II Diabetes. At the same time, the investigation of protein/peptide self-assembly is also active in the design of biological architectures and scaffolds, such as peptide hydrogels, that have many new applications, ranging from regenerative medicine to the delivery of therapeutics. What is more interesting is that such protein/peptide assemblies, e.g. amyloids and hydrogels, share structural similarities, such as formation of highly ordered fibrils with cross ?-sheet arrangements. Studies have shown that self-assembly is regulated by hydrophobic side chain interactions causing the assembly of a distinct hydrophobic core or cluster, which stabilize ?-sheet arrangements. This proposal is founded on the idea that by introducing into the fibril interior a moiety which can produce a light activated charge, we can significantly weaken the hydrophobic interactions crucial to the assembly of aggregates, fibrils, or hydrogel matrices, and potentially disrupt these well-defined structures. This proposal will test this premise by using a photolabile lysine analog, dimethoxy-2-nitrobenzyloxycarbonyl (Lys(nvoc)), which is hydrophobic but yields a charged lysine upon photocleavage, to photo-trigger the dissociation of amyloids and other fibril forming peptide hydrogels. Introducing Lys(nvoc) in the place of other hydrophobic residues is expected to conserve the aggregation propensity prior to irradiation due to the aromatic nature of the photocage, while photocleavage will produce a charge at these positions to induce disassembly of fibrils. The results of these experiments will provide a novel way to manipulate the conformations of otherwise irreversible structures, potentially providing innovative and novel biological applications within amyloid related therapeutic research and/or the rational design of functional bionanomaterials.