Salt-Induced Transitions in the Conformational Ensembles of Intrinsically Disordered Proteins.

Salts modulate the behavior of intrinsically disordered proteins (IDPs) and influence the formation of membraneless organelles through liquid-liquid phase separation (LLPS). In low ionic strength solutions, IDP conformations are perturbed by the screening of electrostatic interactions, independent of the salt identity. In this regime, insight into the IDP behavior can be obtained using the theory for salt-induced transitions in charged polymers. However, salt-specific interactions with the charged and uncharged residues, known as the Hofmeister effect, influence IDP behavior in high ionic strength solutions. There is a lack of reliable theoretical models in high salt concentration regimes to predict the salt effect on IDPs. We propose a simulation methodology using a coarse-grained IDP model and experimentally measured water to salt solution transfer free energies of various chemical groups that allowed us to study the salt-specific transitions induced in the IDPs conformational ensemble. We probed the effect of three different monovalent salts on five IDPs belonging to various polymer classes based on charged residue content. We demonstrate that all of the IDPs of different polymer classes behave as self-avoiding walks (SAWs) at physiological salt concentration. In high salt concentrations, the transitions observed in the IDP conformational ensembles are dependent on the salt used and the IDP sequence and composition. Changing the anion with the cation fixed can result in the IDP transition from a SAW-like behavior to a collapsed globule. An important implication of these results is that a suitable salt can be identified to induce condensation of an IDP through LLPS.