Biomolecular condensates are membraneless compartments that originate through liquid-liquid phase separation (LLPS) of proteins and nucleic acids, enabling cells to regulate biochemical reactions by concentrating molecules in micron-scale domains. Amongst the diverse condensates in cellular contexts, those formed by microtubule-associated proteins (MAPs) are particularly significant because they play a central role in microtubule-controlled cellular processes—intracellular transport, cell division, and organization. Inter or intramolecular interactions in MAPs allow them to undergo LLPS in vitro or when overexpressed in vivo. Plus-end-tracking proteins (+TIPs), a group of structurally and functionally diverse MAPs localize at growing microtubule plus-ends. Previous experimental work hypothesizes that +TIP condensates act as polymerization chaperones in microtubule dynamics; however, their physicochemical properties remain poorly understood. To address this, we developed a multiphase model that integrates the Cahn-Hilliard diffuse interface framework with a Flory-Huggins free-energy scheme and mass-action kinetics. In this model, two MAP species diffuse and interact both with one another and with dynamic microtubule lattice, producing condensate-competent complexes, linking molecular-level protein turnover to thermodynamically driven phase separation. This framework enables us to answer key biological questions—What biophysical conditions drive MAPs to form condensates on the microtubule lattice? How do variations in protein recruitment speed, diffusivity, and binding-unbinding kinetics influence time-to-phase-separation, condensate size and number? How does microtubule dynamics affect condensate morphology? Parameterizing experimentally, we show that +TIPs interaction like EB1-CLIP170 leads to rapid LLPS with fast stabilization into quasi-steady-state condensates, whereas tau proteins produce highly dynamic condensates. Strikingly, incorporation of microtubule lattice anisotropy into the model through MAPs preferential binding to the GTP-tubulin subunits, shows that condensates robustly localize at microtubule-tips—recapitulating +TIPs behavior, while periodic boundary conditions preserve cylindrical geometry of microtubule lattice. Collectively, this mathematical model enables principled biophysical mapping of MAP-driven biomolecular condensation providing a unified predictive framework.
Raha et al. (Sun,) studied this question.