Aggregation of Tau-Fragments in Osmolytic Environment

Dysfunction of the intrinsically disordered Tau protein in the forms of oligomerization and fibril formation can cause numerous neurodegenerative diseases including the Alzheimer's disease. Cellular osmolytic agents such as urea and trimethylamine N-oxide (TMAO) are known for regulating the aggregation propensity of the Tau protein. Interestingly, urea inhibits Tau aggregation while TMAO promotes it. In the present work, we study the effects of mixed urea-TMAO solutions on the aggregation propensities of two fragments of Tau, R2 (²⁷³GKVQIINKKLDL²⁸⁴) and R3 (³⁰⁶VQIVYKPVDLSK³¹⁷), which contain the nucleating segments PHF6* and PHF6 respectively. Using replica-exchange molecular dynamics simulations we find that in the mixed urea-TMAO solution TMAO counteracts the aggregation-inhibiting effects of urea and promotes oligomerization of the peptides. The molecular mechanism behind the counteraction process has been studied by means of the peptide-osmolyte preferential interactions along with the morphological changes in the peptide dimers and oligomers in pure and mixed urea-TMAO solutions.