Multiscale modelling of liquid-liquid and liquid-solid transitions in biomolecular condensates

Speaker

Jorge Reñe Espinosa

Affiliation

Universidad Complutense de Madrid

When
Place

DIPC Josebe Olarra Seminar Room

Host

David De Sancho

Kimika Teorikoa Seminar

The spontaneous self-assembly of proteins and nucleic acids through phase separation into membraneless organelles—known as biomolecular condensates—plays a central role in the functional compartmentalization of the cytoplasm and nucleoplasm [1,2]. However, some condensates undergo an additional phase transition from functional liquid-like states to pathological solid-like assemblies, a process known as condensate ageing [3,4]. Such liquid-to-solid transition is typically driven by the accumulation of cross-β-sheet structures and represents a hallmark of several neurodegenerative disorders [5]. In this talk, I will present the Mpipi-Recharged model [6], a residue-resolution coarse-grained force field that improves the treatment of charge effects in biomolecular condensates containing disordered proteins, multi-domain proteins, and disordered single-stranded RNAs. I will show how the asymmetric coarse-graining of electrostatic interactions enables a more accurate description of the phase behaviour of highly charged condensates, including charge blockiness, stoichiometry variations in complex coacervates, and salt-dependent modulation—without requiring explicit solvation. By combining this model with atomistic simulations, I will discuss how sequence mutations [7], small peptide insertions [8], and RNAs [9] affect the ageing kinetics of protein condensates. Our simulations revealed that introducing negatively charged mutations in the low-complexity domain of FUS—an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—delays the accumulation of inter-protein β-sheets while preserving the phase diagram and viscoelastic properties of the wild-type protein. Conversely, arginine mutations strongly accelerate disorder-to-order β-sheet transitions [7]. I will also show how specific peptide sequences, varying in composition, patterning, and net charge, can notably modulate the phase behaviour and ageing kinetics of phase-separating proteins such as TDP-43 and FUS [8], both related to ALS and FTD. By fine-tuning the balance of aromatic and charged residues within these peptides, we can either enhance or frustrate condensate hardening. Overall, our computational framework aims to provide a powerful approach to analyse how sequence mutations, small molecules, RNAs, or multi-component condensate composition [10] shape the intermolecular interactions governing the stability and time-dependent material properties of biomolecular condensates.


References
[1] Brangwynne et al., Science, vol. 324, no. 5935, pp. 1729–1732, 2009. [2] Boeynaems et al., Trends in Cell Biology, vol. 28, no. 6, pp. 420–435, 2018. [3] Patel et al., Cell, vol. 162, no. 5, pp. 1066–1077, 2015. [4] Molliex et al., Cell, vol. 163, no. 1, pp. 123–133, 2015. [5] Alberti and Hyman, Nature Reviews Molecular Cell Biology, vol. 22, no. 3, pp. 196–213, 2021. [6] Tejedor et al., ACS Central Science, vol. 11, pp. 302−321, 2025. [7] Pedraza et al., Cell Reports Physical Science, 6, 102803, 2025. [8] Sanchez-Burgos et al., Nat. Communs, 16, 8050 2025. [9] Tejedor et al., Nat. Communs., 13, 5717, 2022. [10] Espejo et al., bioRxiv, 10.1101/2025.02.21.639421, 2025

 

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