Self-assembling Nanofiber Vaccines for Neurodegeneration

This project is a collaborative effort to characterize coiled coil or cross-j3 supramolecular nanofibers bearing amyloid-beta and tau sequences to accelerate vaccine development for neurodegenerative disorders. Dr. White's contribution will direct structural characterization of the vaccines using small angle x-ray scattering, powder diffraction, and molecular modeling described in Aim 1. This is a key component for the application of the nanovaccines in preclinical models because conjugation of amyloid-beta and tau to self-associating peptides could render them amyloidogenic and this effect is associated with neurotoxicity and also a complex cascade of inflammatory and immunological responses. The past collaboration between Dr. White and Dr. Rudra (the contact Pl in the NIH application) produced a high impact publication and two additional publications are being prepared for publication. They published one research article together in 2020 in JACS to characterize self-assembly of heterochiral peptides into helical tapes. From Dr. White's immunological assessment, the team will further optimize the design of the coiled-coil or cross-j3 nanofibers to deliver amyloid-beta and tau antigens to develop vaccines against neurodegeneration.

In this Self-assembling Nanofiber Vaccines for Neurodegeneration project, Dr. White will be responsible for the characterization of the different nanofiber vaccines, in solution, using solution x-ray scattering and diffraction techniques. Small-angle x-ray scattering (SAXS) probes the size and shape of the peptide assembly. For fibril-forming peptides, this information can include the thickness and diameter of the fibrils and their heterogeneity. The complementary wide angle x-ray scattering (WAXS) technique looks for long-range order, such as the beta-sheet repeat and helical order present in some fibers.

 

Based on the information from our SAXS, WAXS, and other analyses, Dr. White will develop probable models of the various filaments, and then compare them with the experimental data. These nanofiber assembly models will be optimized using standard Molecular Dynamics Simulations, with NAMD. This will confirm the stability of the model and in the case of filaments, allow the peptide assembly to adopt a characteristic twist and helical diameter which minimizes the energy of the assembly.