Predicting the Interfacial Energy and Morphology of DNA Condensates

Abstract

The physics and morphology of biomolecular condensates formed through liquid-liquid phase separation underpin diverse biological processes, exemplified by the nested organization of nucleoli that facilitates ribosome biogenesis. Here, we develop a theoretical and computational framework to understand and predict multiphase morphologies in DNA-nanostar solutions. Because morphology is governed by interfacial energies between coexisting phases, we combine Flory-Huggins theory with coarse-grained molecular dynamics simulations to examine how these energies depend on key microscopic features of DNA nanostars, including size, valence, bending rigidity, Debye screening length, binding strength, and sticky-end distribution. The phase behavior of DNA nanostars is quantitatively captured by a generalized lattice model, in which the interplay between sticky-end binding energy and conformational entropy determines the effective interactions. Focusing on condensates comprising two dense phases, we find that Janus-like morphologies are ubiquitous because the interfacial energies between the dense and dilute phases, $\gamma_{i\in\{1,2\}}$, are typically comparable. In contrast, nested morphologies are rare as they require a large asymmetry in $\gamma_i$, which arises only for highly dissimilar nanostars such as those differing markedly in valence or size. Moreover, the interfacial energy between the two dense phases, $\gamma_{12}$, can be modulated either discretely, by varying sticky-end distribution, or continuously, by tuning the crosslinker ratio; the former may even eliminate nested configurations. These findings establish physical design principles for constructing complex condensate architectures directly from microscopic molecular parameters.