Salt dependent phase behavior of intrinsically disordered proteins from a coarse-grained model with explicit water and ions.

Multivalent proteins and nucleic acids can self-assemble into biomolecular condensates that contribute to compartmentalize the cell interior. Computer simulations offer a unique view to elucidate the mechanisms and key intermolecular interactions behind the dynamic formation and dissolution of these condensates. In this work, we present a novel approach to include explicit water and salt in sequence-dependent coarse-grained (CG) models for proteins and RNA, enabling the study of biomolecular condensate formation in a salt-dependent manner. Our framework combines a reparameterized version of the HPS protein force field with the monoatomic mW water model and the mW-ion potential for NaCl. We show how our CG model qualitatively captures the experimental radius of the gyration trend of a subset of intrinsically disordered proteins and reproduces the experimental protein concentration and water percentage of the human fused in sarcoma (FUS) low-complexity-domain droplets at physiological salt concentration. Moreover, we perform seeding simulations as a function of salt concentration for two antagonist systems: the engineered peptide PR25 and poly-uridine/poly-arginine mixtures, finding good agreement with their reported in vitro phase behavior with salt concentration in both cases. Taken together, our work represents a step forward towards extending sequence-dependent CG models to include water and salt, and to consider their key role in biomolecular condensate self-assembly.

Druggability of Intrinsically Disordered Proteins.

Although the proteins in all the current major classes considered to be druggable are folded in their native states, intrinsically disordered proteins (IDPs) are becoming attractive candidates for therapeutic intervention by small drug-like molecules. IDPs are challenging targets because they exist as ensembles of structures, thereby making them unsuitable for standard rational drug design approaches, which require the knowledge of the three-dimensional structure of the proteins to be drugged. As we review in this chapter, several different small molecule strategies are currently under investigation to target IDPs, including: (i) to stabilise IDPs in their natively disordered states, (ii) to inhibit interactions with ordered or disordered protein partners, and (iii) to induce allosteric inhibition. In this context, biophysical techniques, including in particular nuclear magnetic resonance (NMR) spectroscopy and small-angle X-ray scattering (SAXS) coupled with molecular dynamics simulations and chemoinformatics approaches, are increasingly used to characterize the structural ensembles of IDPs and the specific interactions that they make with their binding partners. By analysing the results of recent studies, we describe the main structural features that may render IDPs druggable, and describe techniques that can be used for drug discovery programs focused on IDPs.