Predicting the Interfacial Energy and Morphology of DNA Condensates

TL;DR

This paper develops a theoretical and computational framework to predict DNA condensate morphologies by analyzing interfacial energies influenced by nanostar properties, providing design principles for complex biomolecular condensates.

Contribution

It introduces a combined Flory-Huggins and molecular dynamics approach to connect microscopic DNA nanostar features with macroscopic condensate morphologies.

Findings

Janus-like morphologies are common due to similar interfacial energies.

Nested morphologies are rare and require high asymmetry in nanostar properties.

Interfacial energy between dense phases can be tuned to control condensate architecture.

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.