Connecting coil-to-globule transitions to full phase diagrams for intrinsically disordered proteins

Abstract

Phase separation is thought to underlie spatial and temporal organization that is required for controlling biochemical reactions in cells. Multivalence of interaction motifs also known as stickers is a defining feature of proteins that drive phase separation. Intrinsically disordered proteins with stickers uniformly distributed along the linear sequence can serve as scaffold molecules that drive phase separation. The sequence-intrinsic contributions of disordered proteins to phase separation can be discerned by computing or measuring sequence-specific phase diagrams. These help to delineate the combinations of protein concentration and a suitable control parameter such as temperature that support phase separation. Here, we present an approach that combines detailed simulations with a numerical adaptation of an analytical Gaussian cluster theory to enable the calculation of sequence-specific phase diagrams. Our approach leverages the known equivalence between the driving forces for single chain collapse in dilute solutions and the driving forces for phase separation in concentrated solutions. We demonstrate the application of the theory-aided computations through calculation of phase diagrams for a set of archetypal intrinsically disordered low complexity domains. STATEMENT OF SIGNIFICANCEIntrinsically disordered proteins that have the requisite valence of adhesive linear motifs can drive phase separation and give rise to membraneless biomolecular condensates. Knowledge of how phase diagrams vary with amino acid sequence and changes to solution conditions is essential for understanding how proteins contribute to condensate assembly and dissolution. In this work, we introduce a new two-pronged computational approach to predict sequence-specific phase diagrams. This approach starts by extracting key parameters from simulations of single-chain coil-to-globule transitions. We use these parameters in our numerical implementation of the Gaussian cluster theory (GCT) for polymer solutions to construct sequences-specific phase diagrams. The method is efficient and demonstrably accurate and should pave the way for high-throughput assessments of phase behavior.