One of the characteristics of Alzheimer's disease is the presence of neurotoxic deposits in brain tissues, which are largely made up of fibrils comprised of misfolded Amyloid-? (A?) protein. The elucidation of the factors responsible for formation and stabilization of the fibrils and other aggregates is one of the key aspects in discovering the molecular basis of the disease. Our approach will complement and extend the work of other groups that study static structures and bulk properties of the fibrils. Intrinsic flexibility is one of the most important understudied contributions toward stabilization of fibrils and nonfibrillar aggregates. With the abundance of naturally occurring mutations and post-translational modifications of A?, the long- term goal of our research is to identify common dynamical features important in defining aggregation and nucleation propensities. In this proposal, we will conduct site-specific investigations to determine differences in the dynamics between polymorphic states of the fibrils comprised of native A?, as well as in naturally-occurring mutants and post-translational modifications that are known to affect the nucleation process, promote aggregation of the fibrils, and respond in altered fashion to modulation of aggregation by metal ions such as zinc. Special focus will be placed on the unstructured N-terminal domain containing a number of such modifications and regulatory sites. We will utilize deuterium solid-state nuclear magnetic resonance spectroscopy, which is exquisitely sensitive to dynamics, as well as computational modeling necessary for elucidation of dynamical modes and parameters based on the spectroscopic data. The obtained site-specific mechanistic information will shed light on the dynamical modes that are important for driving aggregation and ultimately will contribute to the rational design of pharmaceutical agents that could shunt A? toward less toxic forms of fibrils. This project will greatly enhance research opportunities for undergraduate and master- level students at CU Denver, who are seeking to broaden their education and build-up professional experiences to enter a variety of biomedical fields. The PI has the necessary expertise, passion, and experience to provide outstanding training for these students.
Alzheimer's disease is characterized by toxic deposits (plaques) in brain tissue. Our project contributes to investigations of mechanisms that may be involved in the stabilization and formation of these plaques and elucidation of sites that can be targets of pharmaceutical interventions. In particular, we will focus on the dynamical nature of these molecular aggregates.
| Vugmeyster, Liliya; Griffin, Aaron; Ostrovsky, Dmitry et al. (2018) Correlated motions of C'-N and C?-C? pairs in protonated and per-deuterated GB3. J Biomol NMR 72:39-54 |
| Vugmeyster, Liliya; Ostrovsky, Dmitry (2018) Basic experiments in 2H static NMR for the characterization of protein side-chain dynamics. Methods 148:136-145 |
| Vugmeyster, Liliya; Ostrovsky, Dmitry; Hoatson, Gina L et al. (2017) Solvent-Driven Dynamical Crossover in the Phenylalanine Side-Chain from the Hydrophobic Core of Amyloid Fibrils Detected by 2H NMR Relaxation. J Phys Chem B 121:7267-7275 |
| Vugmeyster, Liliya; Ostrovsky, Dmitry (2017) Comparative Dynamics of Methionine Side-Chain in FMOC-Methionine and in Amyloid Fibrils. Chem Phys Lett 673:108-112 |
| Vugmeyster, Liliya; Ostrovsky, Dmitry (2017) Static solid-state 2H NMR methods in studies of protein side-chain dynamics. Prog Nucl Magn Reson Spectrosc 101:1-17 |
| Vugmeyster, Liliya; Ostrovsky, Dmitry; Clark, Matthew A et al. (2016) Fast Motions of Key Methyl Groups in Amyloid-? Fibrils. Biophys J 111:2135-2148 |
| Vugmeyster, Liliya; Clark, Matthew A; Falconer, Isaac B et al. (2016) Flexibility and Solvation of Amyloid-? Hydrophobic Core. J Biol Chem 291:18484-95 |
| Vugmeyster, Liliya; Ostrovsky, Dmitry; Villafranca, Toni et al. (2015) Dynamics of Hydrophobic Core Phenylalanine Residues Probed by Solid-State Deuteron NMR. J Phys Chem B 119:14892-904 |
