Salts Influence IDP Properties by Modulating the Population of Conformational Clusters.

Salts readily alter the physical properties of intrinsically disordered proteins (IDPs) rich in charged residues. Using a coarse-grained IDP model and computer simulations, we investigated how salts affect the heterogeneous conformational ensemble and segment-level structures of the IDP prothymosin-α, classified as a polyelectrolyte. We show that clusters of conformations with distinct structural features are present within the conformational ensemble of prothymosin-α by projecting it onto a two-dimensional latent space with the aid of autoencoders. Although prothymosin-α is inherently disordered, there are preferred transitions between these clusters of conformations. Changing the salt concentration led to the formation of new conformational clusters or/and the disappearance of existing conformational clusters, contributing to changes in IDP properties. Shuffling the Skopelitian domain (C-terminal sequence) of prothymosin-α, known for its anticancer activity, resulted in a different conformational cluster, indicating that clusters with specific structures are related to a particular IDP function. The multiple conformational clusters with distinct structural features could be correlated to different IDP functions, and salts aid or inhibit these functions by modulating the population of conformations in the clusters.