Binding of Ions to IDPs

 The ensemble of conformations sampled by IDPs is significantly influenced by salt ions, which in turn affect various properties of IDPs such as target binding, protein association, and aggregation. Experimental observations have shown that divalent ions such as Mg2+, Ca2+, Zn2+, and Cu2+ promote the aggregation of IDPs like alpha-synuclein and tau. We investigate the impact of monovalent (NaCl) and divalent (MgCl2) salt ions on the conformational ensemble of two IDPs: prothymosin and tau using computer simulations and a coarse-grained description of IDPs. Prothymosin is a polyelectrolyte with a high fraction of negatively charged IDP, while tau is a polyampholyte with an equal proportion of oppositely charged residues. To assess the effect of salt ions on the ensemble of IDPs, we computed the size of IDPs in terms of R_g in the presence of NaCl and MgC2. We observed that the size of prothymosin- (tau) decreases (increases) with increasing [salt]. The opposite effect of salt on the size of IDPs is due to the specific binding of ions to the polypeptide chain. Prothymosin is a highly negatively charged IDP which have stretches of polyE regions. Due to the Na+ ion binding on polyE stretches (E51-E58, E61-E68, E72-E81, and D93-D98), the repulsion among negatively charged residues decreases and R_g of prothymosin decreases with increasing [salt]. Conversely, the specific ion binding at the acidic N-terminal of tau reduces the attraction among oppositely charged residues and expands the size of tau with increasing [salt].  

(A)  The agreement between experimental (marker) and simulated (line with marker) Kratky plots of  prothymosin (red) and Tau (blue) validates our model. (B) Structure factor as a function of wave vector shows both IDPs behaves as self avoiding random walk (SAW) at physiological conditions.   

Size of the IDPs in terms of radius of gyration, R_g as a function of salt concentration, [salt] in presence of NaCl and MgCl2 for (A) prothymosin and (B) Tau.

The local ion concentration of cations, Na+ as a function of residue index at various [salt] for (A) prothymosin and (C) Tau. The local ion concentration of cations, Mg2+ as a function of residue index at various [salt] for (B) prothymosin and (D) Tau. 

The local ion concentration of anions, Cl-  as a function of residue index at various [salt] for (A) prothymosin and (C) Tau in presence of NaCl. The local ion concentration of cations, Mg2+ as a function of residue index at various [salt] for (B) prothymosin and (D) Tau in presence of MgCl2.