Impact of Guanidinium Hydrochloride on the Shapes of Prothymosin-α and α-Synuclein Is Dramatically Different.

The effects of guanidinium hydrochloride (GdmCl) on two intrinsically disordered proteins (IDPs) are investigated using simulations of the self-organized polymer-IDP (SOP-IDP) model. The impact of GdmCl is taken into account using the molecular transfer model (MTM). We show that due to the dramatic reduction in the stiffness of the highly charged Prothymosin-α (ProTα) with increasing concentration of GdmCl ([GdmCl]), the radius of gyration (R_g) decreases sharply until about 1.0 M. Above 1.0 M, ProTα expands, caused by the swelling effect of GdmCl. In contrast, R_g of α-Synuclein (αSyn) swells as continuously as [GdmCl] increases, with most of the expansion occurring at concentrations less than 0.2 M. Strikingly, the amplitude of the small-angle X-ray scattering (SAXS) profiles for ProTα increases until [GdmCl] ≈ 1.0 M and decreases beyond 1.0 M. The [GdmCl]-dependent SAXS profiles for αSyn, which has a pronounced bump at small wave vector (q ∼ 0.5 nm^-1) at low [GdmCl] (≤0.2 M), monotonically decrease at all values of [GdmCl]. The contrasting behavior predicted by the combination of MTM and SOP-IDP simulations may be qualitatively understood by modeling ProTα as a strongly charged polyelectrolyte with nearly uniform density of charges along the chain contour and αSyn as a nearly neutral polymer, except near the C-terminus, where the uncompensated negatively charged residues are located. The precise predictions for the SAXS profiles as a function of [GdmCl] can be readily tested.