Polymer Theory of Biologically Functional Phase Separations of Intrinsically Disordered Proteins

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Polymer theories as they stand are mainly concerned with homopolymers. Considerably less attention has been paid to heteropolymers. This relative neglect is not only because heteropolymers are more challenging for theory; it has also been a reflection of the limited available experimental data for benchmarking such theories due to difficulties in chemically synthesizing heteropolymers with specific sequences. Consequently, analytical theories for heteropolymers were mostly confined to treating random or simple block copolymers. In contrast, this limitation does not apply to molecular biology wherein accurate synthesis of protein and nucleic acid sequences is routine. In this respect, the recent discovery of the critical and ubiquitous roles of intrinsically disordered protein (IDP) phase separation in a variety of condensed liquid/gel-like bodies/organizations in and around living cells (including membraneless organelles such as stress granules and the nucleolus) constitutes an important impetus and offers exciting prospects for developing polymer theories for sequence-dependent heteropolymer phase properties. Despite the intense interest generated by the observation of IDP phase separations, physical understanding of the phenomenon is only at its infancy. Mean-field Flory-Huggins (FH) and Overbeek-Voorn theories have been invoked, but they alone are insufficient because an account for sequence-specificity is lacking. In this context, the applicant's group made the first breakthrough by applying the random-phase approximation (RPA) polymer theory to address how phase behaviors of polyampholytes depend on the charge patterns along their chain sequences. We showed further that the propensity for a neutral polyampholyte to phase separate in a multiple-chain setting is strongly and negatively correlated with its conformational dimensions as an individual chain. Most recently, using an extension of RPA, we found also that the tendency for chains of two IDP sequences to mix or demix upon phase separation is correlated with the difference in their charge patterns. Building on these seminal advances, we will develop further analytical formulations for sequence-dependent effects of not only electrostatics but also other forms of inter-monomer interactions as well as local variations of chain stiffness. In order to afford a better account of IDPs with high net charge densities and interactions with short spatial ranges such as hydrophobicity, we will device novel techniques to apply variational methods for renormalized Kuhn lengths to circumvent certain shortcomings of RPA theories. By using our theory to rationalize the rapidly expanding repertoire of experimental data on IDP phase separation and to make testable predictions, the proposed effort will provide valuable insights into cellular compartmentalization and can also facilitate development of new materials.