Interplay of Homotypic and Heterotypic Interactions in the Assembly and Phase Separation of Biomolecules

Abstract

Biomolecular condensates have been recognized as prominent cellular constructs which participate in crucial processes necessary for the survival and maintenance of the cell. Condensation occurs via interactions between a variety of biomolecules which themselves are made up of multiple diverse domains. Contributions from homotypic interactions i.e., interactions between chemically similar entities and heterotypic interactions i.e., interactions between chemically dissimilar entities come together to decide the formation of a condensate, its composition and morphology. In this work, we enumerate the possible scenarios of condensate formation with varying contributions from homotypic and heterotypic interactions and then focus on specific systems of biological relevance. The studies are conducted using coarse grained models developed for efficiently capturing the formation of condensates in molecular dynamics simulations. We first present the various possible scenarios using simple homopolymer models of multicomponent systems and multidomain single component systems with varying homo and heterotypic interaction strengths. Next, we focus on the contributions of homo and heterotypic interactions in forming RNA-protein condensates and how changing the protein sequence perturbs the interaction network to change condensate morphology. Following that, we focus on the assembly of a single protein, the Polyhomeotic-proximal (Ph-p) which consists of diverse domains where each domain has its own distinct structural and chemical properties. The homotypic and heterotypic interactions between these different domains are investigated and characterized to reveal the mechanism which leads to Ph-p assembly. We also discover how changes in intrinsically disordered regions between different animal models have changed the homotypic and heterotypic interaction landscape.