| Popis: |
Unregulated growth of amyloid plaques is associated with a large number of human degenerative diseases such as Alzheimer's Disease or Type II Diabetes, where the pathological misfolding and subsequent accumulation of amyloid plaques inhibits the proper functioning of nearby cells. Simulations and experiments have revealed that amyloid aggregates are highly energy-minimized structures that are difficult to molecularly disassemble without causing further physiological duress. However, recent studies have identified a 24-amino acid mitochondrial peptide named Humanin (seq: MAPRGFSCLLLLTSEIDLPVKRRA) that provides neuroprotection to mice by reducing the formation of amyloid-beta aggregates in their brains, though the effects are thought to translate to other amyloid systems as well. Due to the intrinsically disordered nature of Humanin, experimental studies have struggled to characterize its interaction with other proteins, especially those that are also intrinsically disordered. To better understand the molecular basis for Humanin interactions with amyloid proteins, we performed a combination of replica-exchange molecular dynamics simulations and ThT fluorescence spectroscopy, where we identified the molecular interactions of Humanin and IAPP. We report a number of free-energy landscapes of hydrated IAPP and Humanin in isolation, and in the presence of one another, to better understand how Humanin and other peptide analogs can be used to inhibit amyloid aggregation in a wide variety of environments. |
