Monitoring the Mechanism of Fiber Assembly of AB Peptides in Alzheimer's Disease (AD) by Two-Dimensional Ultraviolet (2DUV) Spectroscopy

Abstract

Understanding the aggregation mechanism of amyloid fibrils is a critical step in the investigation of several neurodegenerative disorders associated with the misfolding of proteins. In a previous study (Rojas et al., JMB 2010 404, 537--552), the growth mechanism of β-amyloid peptide fibrils which is associated with Alzheimer's disease (AD), was successfully modeled by using a physics-based coarse-grained united-residue model and molecular dynamics (MD) simulations. We report a simulation study of coherent two-dimensional chiral signals based on the trajectories obtained by Rojas et al. to monitor this growth mechanism at different simulation times. Far ultraviolet signals (FUV)(λ = 190--250 nm) originated from the backbone nπ∗ and ππ∗ transitions, and near ultraviolet signals (NUV) ( λ >= 250 nm) are associated with aromatic side-chains (Phe and Tyr). These signals display distinct cross peak patterns in the two-dimensional spectra that can be used, in combination with MD, to monitor local dynamics and conformational changes in the secondary structure of Aβ peptides during the aggregation process. 2DUV total chiral signals in the aggregation process are combinations of subset of chiral signals from a monomer Aβ peptide, an amyloid fibril and the interactions between them.