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bioRxiv · 10.1101/2024.08.28.610132

Phase behaviour of hnRNPA1 low-complexity domain mutants described by different sequence-dependent models

Feito, A.·Sanchez-Burgos, I. R.·Tejero, I.·Sanz, E.·Rey, A.·Collepardo-Guevara, R.·Tejedor, A. R.·Rene Espinosa, J.
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Abstract

Intracellular liquid-liquid phase separation (LLPS) of proteins and nucleic acids is a fundamental mechanism by which cells compartmentalize their components and perform essential biological functions. Molecular simulations play a crucial role in providing microscopic insights into the physicochemical processes driving this phenomenon. In this study, we systematically compare six state-of-the-art sequence-dependent, residue-resolution models to evaluate their performance in reproducing the phase behaviour and material properties of condensates formed by seven variants of the low-complexity domain (LCD) of the hnRNPA1 protein (A1-LCD)--a protein implicated in the pathological liquid-to-solid transition of stress granules. Specifically, we assess the HPS, HPS-cation-{pi}, HPS-Urry, CALVADOS2, Mpipi, and Mpipi-Recharged models in their predictions of the condensate saturation concentration, critical solution temperature, and condensate viscosity for the A1-LCD variants. Our analyses demonstrate that, among the tested models, Mpipi, Mpipi-Recharged, and CALVADOS2 provide accurate descriptions of the critical solution temperatures and saturation concentrations for the various A1-LCD variants tested. Regarding the prediction of material properties for condensates of A1-LCD and its variants, Mpipi-Recharged stands out as the most reliable model. Overall, this study benchmarks a range of residue-resolution coarse-grained models for the study of the thermodynamic stability and material properties of condensates and establishes a direct link between their performance and the ranking of intermolecular interactions these models consider.

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Feito, A., Sanchez-Burgos, I. R., Tejero, I., Sanz, E., Rey, A., Collepardo-Guevara, R., Tejedor, A. R., Rene Espinosa, J.. 2024-08-29. Phase behaviour of hnRNPA1 low-complexity domain mutants described by different sequence-dependent models. https://doi.org/10.1101/2024.08.28.610132

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