The aggregation of amyloid peptides into soluble oligomers and fibrils is a hallmark of Alzheimer’s disease. The interaction of these aggregates with the cell membrane accounts for an important mechanism of toxicity wherein oligomers can form pores in lipid membranes and amyloid fibrils can induce lipid loss. As monomers, i.e., individual peptides, have been found to be mostly nontoxic, the development of strategies to inhibit aggregation has the potential to translate into the development of new preventive treatments for Alzheimer’s disease. These efforts require, however, a deep understanding of the interactions accounting for amyloid aggregation. Previously, the aggregation of peptides in bulk solution, i.e., primary nucleation, was assumed to be the main mechanism accounting for the formation of oligomers. More recently, this assumption was reassessed by careful kinetic experiments, which can only be explained quantitatively assuming that most oligomers form on the surface of existing fibrils in a process known as secondary nucleation. Currently, there is a critical lack of understanding of the molecular interactions and pathways accounting for secondary nucleation. This remains a serious impediment for the rational design of drugs that can inhibit oligomerization on the fibril surface. This proposal uses innovative all-atom molecular dynamics simulations complemented with biophysical and biochemical experiments to fill this knowledge gap. It takes advantage of improvements in the development of force fields as well as in the enhanced performance of today’s supercomputers that can now track the position of many atoms (~250,000 atoms) for a long-time (>10 μs). Moreover, this project provides opportunities for undergraduate students to participate in all aspects of this research including setting up, running, and analyzing simulations in different supercomputer clusters. All-atom simulations will be used in aim 1 of this project to determine how the peptide sequence affects pathways and interactions accounting for oligomerization in bulk solution. Simulations in aims 2 and 3 will be performed in large boxes containing a seeded fibril. In aim 2, a systematic study will be carried out to shed light into effects of the fibril surface and the peptide sequence on fibril elongation. Oligomerization pathways at the fibril surface, i.e., secondary nucleation, will be studied in aim 3. A comparative study of oligomerization pathways in primary and secondary nucleation will be performed to determine the interactions enabling the fibril surface to catalyze the aggregation process.
|Effective start/end date||9/22/22 → 8/31/25|
- National Institute of General Medical Sciences: $63,760.00
- National Institute of General Medical Sciences: $474,325.00
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