Synergistic approaches unraveling regulation and aggregation of intrinsically disordered β-amyloids implicated in Alzheimer's disease.

Abstract

Alzheimer's disease is a severe brain illness that causes vast numbers of nerve cells in the brain to die, driven by the production and deposition of amyloid beta (Aβ) peptides. Intrinsically disordered proteins (IDPs) generally lack stable structures and are abundant in nature. Aβ peptide is a well-known IDP with a wide range of oligomeric forms. Dysfunctions in Aβ lead to oligomerization, formation of fibrils, and neurodegenerative disorders or other forms of dementia. In this study, we used replica exchange molecular dynamics (REMD) to elucidate the roles of different osmolytes, particularly urea and trimethylamine N-oxide (TMAO), to study shifts in IDP populations. REMD samples the conformational space efficiently and at physiologically relevant temperatures, compared to conventional molecular dynamics that sample at a constant temperature. Urea is known to minimize the aggregation process, while TMAO is beneficial for its stabilizing action. The two osmolytes displayed characteristic effects on Aβ peptides and resulted in progressive modulation of conformations. The present study underlines the hypothesis of "modulation of conformational ensembles" to explain the regulation and aggregation of IDPs.