Biology subjects

Luengo-Marquez, J.

Publications and source records attributed to Luengo-Marquez, J..

3 recordsLinked to original sources

bioRxiv2026

RNA2PS: A sequence-specific coarse-grained RNA model linking structure, thermodynamics and phase separation

RNA plays a central role in the formation and regulation of biomolecular condensates, yet a quantitative understanding of how RNA sequence, structure, and thermodynamics jointly determine phase behaviour, particularly in repeat expansion RNAs, remains incomplete. Here, we introduce RNA2PS, a sequence-specific RNA coarse-grained model for phase-separation that predicts RNA structure from sequence, achieving quantitative agreement for both single-stranded conformations and duplex helical geometry relative to crystallographic PDB structures. RNA2PS represents each nucleotide by two beads that separate the phosphate-ribose backbone from the base. This representation decouples electrostatic interactions from directional base pairing, while explicitly incorporating strand polarity (5' [->] 3') and local sequence context at the trimer level. Canonical and wobble base pairing are modelled through a multi-body potential with sequence-dependent coordination. Importantly, RNA2PS captures sequence-dependent duplex stability at the nearest-neighbour level and reproduces experimental melting temperatures across a diverse set of sequences. RNA2PS shows that phase separation of trinucleotide repeat RNAs is governed by transient inter-strand duplexes that form reversible cross-links. Competition between intra- and intermolecular base pairing regulates the density of labile RNA-RNA interactions, giving rise to strong sequence- and length-dependent differences in condensation that reproduce cellular RNA foci formation. Overall, RNA2PS provides a near-quantitative predictive framework that links sequence-encoded hybridization thermodynamics to mesoscale condensation of pure RNA sequences.

biophysics↗

bioRxiv2026

Interplay between Local Diffusion, Concentration, and Inter-Protein Alignment Promotes Cross-β-Sheet Transitions at Condensate Interfaces

The interface separating a biomolecular condensate from its surroundings is increasingly recognised as a unique physical and chemical environment that actively regulates condensate behaviour. It controls surface tension, molecular organisation and chemical reactivity, and is also where pathological ageing often begins, with several proteins nucleating cross-{beta}-sheet fibrils preferentially at condensate surfaces. But does ageing emerge there because of protein-specific chemistry, or a more general physical mechanism? Using coarse-grained molecular dynamics simulations, we show that cross-{beta}-sheet nucleation generically occurs preferentially at condensate interfaces across systems of increasing chemical complexity, from simple homopolymers to patterned amphiphilic sequences. In all systems studied, interface-driven ageing has a common physical origin and can be further modulated, but not driven, by protein sequence. Specifically, terminal domains at the condensate interface gain mobility while remaining densely packed and mutually aligned, creating favourable conditions for {beta}-sheet nucleation. Ageing is amplified in amphiphilic sequences, where hydrophilic regions act as surfactants facing the dilute phase, while aggregation-prone hydrophobic domains cluster just beneath the surface, concentrating the nucleation there. This surfactant-like organisation lowers the interfacial free energy, which falls systematically as sequence asymmetry grows. By linking molecular interactions to mesoscale behaviour, these results cast the interface as a central regulator of ageing and reveal a sequence-independent physical mechanism for the liquid-to-solid transition underlying pathological aggregation in biomolecular condensates.

biophysics↗

bioRxiv2023

Systematic comparison of Amber force fields for the mechanical properties of double-stranded DNA

AbstractThe response of double-stranded DNA to external mechanical stress plays a central role in its interactions with the protein machinery in the cell. Modern atomistic force fields have been shown to provide highly-accurate predictions for the fine structural features of the duplex. In contrast, and despite their pivotal function, less attention has been devoted to the accuracy in the prediction of the elastic parameters. Several reports have addressed the flexibility of double-stranded DNA via all-atom molecular dynamics, yet the collected information is insufficient to have a clear understanding of the relative performance of the various force fields. In this work, we fill this gap by performing a systematic study in which several systems, characterized by different sequence contexts, are simulated with the most up-to-date force fields, bcs1 and OL15, in the presence of external forces with increasing magnitude. Analysis of our results, together with their comparison with previous work focused on bsc0, allows us to unveil the differences in the predicted rigidity between the newest force fields, and suggests a road map to test their performance against experiments.

biophysics↗