Improved predictions of phase behaviour of intrinsically disordered proteins by tuning the interaction range.

The formation and viscoelastic properties of condensates of intrinsically disordered proteins (IDPs) is dictated by amino acid sequence and solution conditions. Because of the involvement of biomolecular condensates in cell physiology and disease, advancing our understanding of the relationship between protein sequence and phase separation (PS) may have important implications in the formulation of new therapeutic hypotheses. Here, we present CALVADOS 2, a coarse-grained model of IDPs that accurately predicts conformational properties and propensities to undergo PS for diverse sequences and solution conditions. In particular, we systematically study the effect of varying the range of the nonionic interactions and use our findings to improve the temperature scale of the model. We further optimize the residue-specific model parameters against experimental data on the conformational properties of 55 proteins, while also leveraging 70 hydrophobicity scales from the literature to avoid overfitting the training data. Extensive testing shows that the model accurately predicts chain compaction and PS propensity for sequences of diverse length and charge patterning, as well as at different temperatures and salt concentrations.