Towards transferable explicit-solvent coarse-grained models for biomolecular condensates
Abstract
Biomolecular condensates formed by intrinsically disordered proteins require molecular models that accurately describe proteins in both dilute solution and condensed phases. Explicit-solvent coarse-grained models offer an attractive balance between chemical resolution and computational efficiency. Yet, it remains unclear whether improving dilute-state properties is sufficient to obtain an accurate description of condensates. Here, we address this question by introducing minimal modifications to the Martini 3 force field that combine recent advances in bonded interactions with refined protein-water interactions and strengthened glycine self-interactions, while preserving the underlying chemical transferability of the model. The resulting model substantially improves the description of single-chain conformations across a diverse benchmark of disordered proteins. We then investigate phase separation of the well-characterized low-complexity domain of heterogeneous nuclear ribonucleoprotein A1 and its sequence variants. The model reproduces several key physicochemical properties of biomolecular condensates, including chain expansion in the dense phase, sequence-dependent intermolecular contacts, protein diffusion and its relation to single-chain dimensions, and hydration, while revealing quantitative limitations in condensate density, phase equilibria, and ion partitioning. Our results show that improving dilute-state behaviour translates into a better description of condensed-phase properties, including condensate density, but is not sufficient to quantitatively reproduce the equilibrium between the dilute and dense phases.
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BibTeX
@misc{toplek2026towards,
title = {{Towards transferable explicit-solvent coarse-grained models for biomolecular condensates}},
author = {Fran Bačić Toplek and Luis Borges-Araujo and Kresten Lindorff-Larsen and Ralf Everaers and Paulo C T Souza and Tatiana I Morozova},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.747511},
url = {https://hal.science/hal-05787670v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Towards transferable explicit-solvent coarse-grained models for biomolecular condensates
AU - Fran Bačić Toplek
AU - Luis Borges-Araujo
AU - Kresten Lindorff-Larsen
AU - Ralf Everaers
AU - Paulo C T Souza
AU - Tatiana I Morozova
PY - 2026
DA - 2026/08/29
PB - HAL
DO - 10.64898/2026.08.27.747511
UR - https://hal.science/hal-05787670v1
AB - Biomolecular condensates formed by intrinsically disordered proteins require molecular models that accurately describe proteins in both dilute solution and condensed phases. Explicit-solvent coarse-grained models offer an attractive balance between chemical resolution and computational efficiency. Yet, it remains unclear whether improving dilute-state properties is sufficient to obtain an accurate description of condensates. Here, we address this question by introducing minimal modifications to the Martini 3 force field that combine recent advances in bonded interactions with refined protein-water interactions and strengthened glycine self-interactions, while preserving the underlying chemical transferability of the model. The resulting model substantially improves the description of single-chain conformations across a diverse benchmark of disordered proteins. We then investigate phase separation of the well-characterized low-complexity domain of heterogeneous nuclear ribonucleoprotein A1 and its sequence variants. The model reproduces several key physicochemical properties of biomolecular condensates, including chain expansion in the dense phase, sequence-dependent intermolecular contacts, protein diffusion and its relation to single-chain dimensions, and hydration, while revealing quantitative limitations in condensate density, phase equilibria, and ion partitioning. Our results show that improving dilute-state behaviour translates into a better description of condensed-phase properties, including condensate density, but is not sufficient to quantitatively reproduce the equilibrium between the dilute and dense phases.
ER -