pH Effect on Prothymosin

Prothymosin, a 111-residue acidic nuclear intrinsically disordered protein, is involved in various functions such as cell proliferation, chromatin remodeling, and proapoptotic activity. Experiments have shown that prothymosin exists as a random coil due to the presence of a high fraction of charged residues and adopts a partially compact state at low pH due to the neutralization of negatively charged residues. At low pH, prothymosin can aggregate and form regular amyloid fibrils. The formation of amyloid fibrils is associated with various diseases such as Alzheimer's disease, Parkinson's disease, diabetes, cancer, etc.

Effect of pH on each segment of prothymosin. (A) The difference in contact map between pH = 2.5 and 7.5 for prothymosin where color bar denotes the probability of contact formation. Positive values (red) correspond to an increase in contact formation and negative values (blue) correspond to a decrease in contact formation. Representative conformation of prothymosin at pH = 7.5 and 2.5 is shown in (B) and (C) where three segments are denoted as N-ter (M1-E40) in blue, intermediate E-region (E41-D80) in red and C-ter (E81-D111) in green. (D) Rescaled radius of gyration for different segments with varying pH where light shaded bar and solid bar with line correspond to pH = 2.5 and 7.5, respectively.

Percentage of beta-sheet content as a function of residue at pH = 7.5 (red) and pH = 2.5 (blue). The beta-sheet content increases at low pH in the intermediate region (E-region i.e. E41-D80) shown in green rectangle.

Fraction of interchain contact as a function of time is shown at pH = 2.5 for N* and non-N* states. Three representative independent trajectories with two-dashed lines in cyan, magenta, and yellow are initiated from N* states. The three representative independent trajectories with solid lines in red, green, and blue are initiated from non-N* states. The plot suggests that the trajectories initiated with N* states reach f_{contact} = 1 i.e. forms dimer within 0 - 1.5 microseconds whereas the trajectories started with non-N* states do approach towards f_{contact} = 1 and mostly remain in monomer state within the simulation timescale.