Salt Induced Transitions in the Conformational Ensembles of Intrinsically Disordered Proteins

Abstract

Salts modulate the behavior of intrinsically disordered proteins (IDPs). In low ionic strength solutions, IDP conformations are primarily perturbed by the screening of electrostatic interactions, independent of the identity of the salt. In this regime, insight into the IDP behavior can be obtained using the theory for salt-induced transitions in charged polymers. However, in high ionic strength solutions, salt-specific interactions with the charged and uncharged residues, known as the Hofmeister effect, influence IDP behavior. There is a lack of reliable theoretical models in high salt concentration regimes to predict the salt effect on IDPs. Using a coarse-grained simulation model for the IDPs and experimentally measured water to salt solution transfer free-energies of various chemical groups, we studied the salt-specific transitions induced in the IDPs conformational ensemble. We probed the effect of three different salts, ranging from protective osmolyte to denaturant, on five IDPs belonging to various polymer classes classified based on charge content. The transitions observed in the IDP conformational ensembles are dependent on the salt used and the IDP polymer class. An important implication of these results is that a suitable salt can be identified to induce condensation of an IDP through liquid-liquid phase separation.

pH Induced Switch in the Conformational Ensemble of an Intrinsically Disordered Protein Prothymosin-αand Its Implications to Amyloid Fibril Formation

“…In the absence of the salt at neutral pH, proT α behaves as a rod-like chain with ν ≈ 1.0. 14 The CD and SAXS 11,24 experiments also confirm that proT α exists in an extended state at neutral pH. However, the negatively charged residues become protonated with decreasing pH, and the chain size compacts to behave like an ideal chain (Figure 1B).…”

“…We used a coarse-grained SOP-IDP 14,36 model to study the pH effect on proT α . In this model, each residue is represented by two beads, one for the backbone atoms and another for the side chain atoms.…”

“…Aberrant behavior of IDPs forming amyloid fibrils through aggregation leads to diseases 7,8 such as Alzheimer’s, Parkinson’s, tauopathy, and cancer. External factors 9 such as temperature, 10 pH, 11,12 salts, 13,14 cosolvents, 15–17 crowder 17,18 etc. modulate the conformational ensemble as well as the aggregation propensities 18–23 of IDPs.…”

“…25,26 The conformational ensemble of proT α is modulated using salt and pH through the variation of electrostatic interactions. 11,13,14 Small-angle X-ray scattering (SAXS) experiments 11 showed that proT α changes its conformation from random coil to a partially collapsed state on pH change from neutral to acidic. It was also observed that at low pH, proT α aggregates into regular elongated amyloid fibrils.…”

“…External factors 9 such as temperature, 10 pH, 11,12 salts, 13,14 cosolvents, 15-17 crowder 17,18 etc. modulate the conformational ensemble as well as the aggregation propensities [18][19][20][21][22][23] of IDPs.…”