In this study, we integrate atomistic molecular dynamics (MD) simulations with coarse-grained modeling to unravel the physicochemical determinants of small-molecule partitioning into model condensates. Our simulations reveal that hydrophobicity, previously considered a dominant factor in partitioning [3], plays a key role for condensates enriched in hydrophobic residues. However, in more polar condensates, solubility—and by extension, compound–solvent interactions—emerges as a stronger regulator of partitioning behavior. This shift highlights the importance of the condensate’s chemical environment in modulating small molecule uptake. Furthermore, we predict that polar condensates demonstrate greater selectivity, preferentially enriching specific classes of compounds. This selectivity suggests a promising avenue for the development of condensate-targeted therapeutics with enhanced specificity.
To generalize these findings and enable rapid predictions across diverse systems, we introduce MAPPS (MinimAl models for Prediction of small-molecule Partitioning into biomolecular condensateS), a computational framework that captures key physicochemical features governing partitioning. MAPPS is built upon Mpipi [4], our previously developed coarse-grained model for predicting protein phase behavior. We show that MAPPS can accurately reproduce partition coefficients obtained from atomistic simulations, both in model peptide systems and in condensates composed of the low-complexity domain (LCD) of the RNA-binding protein FUS [5]. Applying MAPPS to a range of LCD-based condensates reveals that subtle variations in protein sequence can influence condensate selectivity, thereby shaping small-molecule partitioning profiles.
Overall, our findings emphasize that partitioning is not solely a function of small-molecule hydrophobicity or size, but is also modulated by the nuanced interplay between compound properties and condensate chemical environment. This work lays the groundwork for predictive, sequence-informed models of small-molecule uptake into condensates and provides a foundation for structure-based design of condensate-targeted drugs.
[1] Banani, Salman F., et al. "Biomolecular condensates: organizers of cellular biochemistry." Nature reviews Molecular cell biology 18.5 (2017): 285-298.
[2] Boeynaems, Steven, et al. "Protein phase separation: a new phase in cell biology." Trends in cell biology 28.6 (2018): 420-435.
[3] Ambadi Thody, Sabareesan, et al. "Small-molecule properties define partitioning into biomolecular condensates." Nature Chemistry 16.11 (2024): 1794-1802.
[4] Joseph, Jerelle A., et al. "Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy." Nature computational science 1.11 (2021): 732-743.
[5] Patel, Avinash, et al. "A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation." Cell 162.5 (2015): 1066-1077.