Ameliorating amyloid aggregation through osmolytes as a probable therapeutic molecule against Alzheimer's disease and type 2 diabetes.

Large numbers of neurological and metabolic disorders occurring in humans are induced by the aberrant growth of aggregated or misfolded proteins. Alzheimer's disease (AD) and type 2 diabetes (T2D) are two of the most prevalent disorders that lead to toxic protofibrils of amyloid beta (Aβ) and human islet amyloid polypeptide (hIAPP) in the form of intrinsically disordered proteins (IDPs). IDPs are important functional proteins or peptides that have no common structures and are found in various organisms; they play an imperative role in multiple biological mechanisms, changing their folding and unfolding patterns depending on the environment. Osmolytes are low molecular weight naturally occurring small molecules present in almost all organisms that act as denaturants or counter-denaturants, helping to alter the environmental surroundings under stressful or pathological conditions. These molecules aid in imparting steadiness on accumulated proteins and defending them from aggregating. In the current study, we performed an advanced sampling technique, replica-exchange molecular dynamics (REMD) simulations, to investigate the activities of osmolytes, with guanidine hydrochloride (G-HCL) acting as a denaturant and l-proline (l-PRO) acting as a counter-denaturant, and to explore the regulation and aggregation of Aβ and hIAPP. We report that G-HCL and l-PRO have noticeable natural effects on Aβ and hIAPP, leading to conformation modulation. Our results highlight that G-HCL attenuates peptide aggregation and transitions peptides into unfolded conformations, while l-PRO helps produce folded conformations of Aβ and hIAPP.