PROJECT ZeroFold ║ ║ ║ ║ The Protein Structure Hidden ║ ║ for 70 Years ║ ║ ║ ║ A Universal Target for ║ ║ Neurodegenerative Disease ║ ║

Abstract

PROJECT ZeroFold proposes that protein aggregation diseases share a universal structural intermediate, the alpha sheet conformation, derivable from geometric first principles. We have developed the Spectrum Closure Framework, which derives all physical scales—including the fine structure constant and all protein secondary structures—from three geometric invariants. The framework predicts the alpha sheet (φ=-80°, ψ=+80°) as a flat pleated structure that forms during the transition from native fold to amyloid fibril. Critically, this structure is predicted to appear in all protein aggregation processes regardless of the starting protein, explaining why diverse proteins (Aβ, α-synuclein, tau, prion protein, huntingtin) form morphologically similar fibrils. We propose to: (1) synthesize peptides designed to adopt alpha sheet conformation, (2) characterize these peptides by circular dichroism, NMR spectroscopy, and X-ray crystallography, (3) develop alpha sheet-specific antibodies, and (4) test for alpha sheet presence in disease models. Success would establish the first universal target for amyloid disease therapeutics, with potential applications in Alzheimer's disease, Parkinson's disease, ALS, prion diseases, and systemic amyloidosis.