2025 AIChE Annual Meeting

(477a) Physics-Based Modeling of RNA Phase Behavior

Authors

Jerelle Joseph, Princeton
Nucleic Acids (NAs), especially RNA, are ubiquitous components of biomolecular condensates. Despite the common existence of RNA in biologically relevant condensates, the effect of RNA–RNA interactions on condensate material properties and the inherent phase separation characteristics of RNA are less understood. By innovating and implementing multiscale modeling approaches, we investigate the functional implications of RNA–RNA interactions in viral replication t and the role of the 2'-OH group in regulating RNA phase separation and percolation. First, we use a residue-resolution coarse-grained RNA model [1] to study how RNA sequence complementarity regulates the condensate material properties [2]. With co-condensating protein, RNAs with high complementarity form heterogeneous, networked condensates, whereas low-complementarity RNAs yield liquid-like droplets in experiments. Our coarse-grained simulations predict that such morphologies are controlled by the trans RNA contact density; highlighting that condensate material properties can be engineered by modulating trans RNA interactions. Second, we leverage all-atom simulations to study the role of the 2’-OH group in the ribose in RNA phase separation and percolation transitions [3]. RNA exhibits phase separation and percolation transitions in a Mg²⁺-dependent manner. However, 2’-deoxyribose (DNA) inhibits condensation and dynamical arrest, while 2’-O-methylation reduces phase separation propensity. Our simulations attribute these effects to solvation differences and chain flexibility, underscoring sugar chemistry’s role in tuning nucleic acid phase behavior. Taken together, our work highlights the collaborative role of RNA sequence, intermolecular interactions, and chemical modifications in regulating condensate formation. These insights can inform strategies to engineer synthetic condensates and target pathological aggregates in neurodegeneration and viral infection.

References:

[1] Dilimulati Aierken, and Jerelle A. Joseph. Accelerated Simulations Reveal Physicochemical Factors Governing Stability and Composition of RNA Clusters. Journal of Chemical Theory and Computation 2024 20 (22), 10209-10222.

[2] Dilimulati Aierken, Vita Zhang, Rachel Sealfon, John C. Marecki, Kevin D. Raney, Amy S. Gladfelter, Jerelle A. Joseph, and Christine A. Roden. Biomolecular condensates control and are defined by RNA-RNA interactions that arise in viral replication. bioRxiv 2024, DOI: 10.1101/2024.12.23.630161.

[3] Gable M. Wadsworth, Dilimulati Aierken, George M. Thurston, Jerelle A. Joseph, and Priya R. Banerjee. The Critical Role of the 2'-OH group in Phase Separation and Percolation Transitions of RNA. bioRxiv 2025, DOI: 10.1101/2025.02.26.638501.