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. We also leverage theories to compute sequence-specific percolation lines and thereby provide a thermodynamic framework for hardening transitions that have been observed for many biomolecular condensates.
|Number of pages||17|
|Publication status||Published - 21 Jul 2020|
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