Effect of TMAO and Urea on Dimers and Tetramers of Amyloidogenic Heptapeptides (

Human islet amyloid polypeptide (hIAPP) (1-37) is an intrinsically disordered protein that is released with insulin by β-cells found in the pancreas. Under certain environmental conditions, hIAPP can aggregate, which leads to β-cell death. FGAILSS (23-29) residues of the hIAPP protein form β sheets, which may be toxic species in type 2 diabetes (T2D) patients. All-atom molecular dynamics (MD) simulations have been used to analyze the effect of two distinct types of osmolytes trimethylamine N-oxide (TMAO) and urea on two and four FGAILSS heptapeptides. TMAO leads the individual peptide toward an extended conformation with a higher radius of gyration and favors the formation of antiparallel β-sheets with an increase in its concentration. However, urea mostly shows compaction of individual peptides except at 4.0 M in the case of a tetramer but does not show aggregation behavior as a whole. TMAO leads both the dimer and tetramer toward the native state with an increase in its concentration. Moreover, both the dimer and tetramer show irregular behavior in urea. The tetramer in 4.0 M urea shows the maximum fraction of native contacts due to the formation of antiparallel β-sheets. This formation of antiparallel β-sheets favors the aggregation of peptides. TMAO forms a smaller number of hydrogen bonds with peptides as compared to urea as the exclusion of TMAO and accumulation of urea around the peptides have occurred in the first solvation shell (FSS). Principal component analysis (PCA) results suggest that the minima in the free energy landscape (FEL) plot are homogeneous for a particular conformation in TMAO with smaller basins, while in urea, the dimer shows minima mostly for extended conformations. For a 4.0 M urea concentration, the tetramer shows the minimum for antiparallel β-sheets, which indicates the aggregation behavior of the tetramer, and for a higher concentration, it shows minima with wider basins of extended conformations.