Event Description
Title: The Effect of Amino Acid SubstitutionsK16A and K28A on Amyloid β-Protein Self-Assembly
Physics Major: Nick Kruczek
Abstract: Alzheimer's disease (AD) is the leading cause of dementia among elderly. The build-up of amyloid beta (AB) aggregates in the brain is associated with the onset of AD, an affliction that leads to a massive loss of neurons. Of the two predominant AB alloforms in the brain, AB40 and AB42, the latter forms more toxic assemblies. Molecular tweezers, that specifically bind lysine (K) residues, were recently shown to inhibit AB toxicity and the effect of two amino acid substitutions, K16A and K28A, was shown to significantly affect the resulting toxicity.
Discrete molecular dynamics (DMD) simulations combined with the four-bead peptide model in implicit solvent were shown to reproduce the experimentally observed AB40 and AB42 oligomer size distributions. Here, we applied this DMD approach to simulate oligomer formation of the AB40 and AB42 mutants. This approach allows us to calculate oligomer size distributions that can be directly compared to experimental distributions and can also be used to see statistically significant differences between the mutant peptides and their wild type counterparts. These differences correspond to fundamentally different structures that can be explored in further detail through analysis of higher order structures, the solvent accessible surface area, and others. Studying the differences found in [K16A]AB and [K28A]AB will provide clues to how toxicity of AB oligomers is affected by their structure and what role the two Lys residues play in the assembly. The resulting structure--toxicity relationship will in turn provide important information needed for development of drugs that specifically target AB oligomers.
Advisor: Brigita Urbanc |
