Time-Dependent Material Properties of Aging Biomolecular Condensates from Different Viscoelasticity Measurements in Molecular Dynamics Simulations

AR Tejedor and R Collepardo-Guevara and J Ramírez and JR Espínosa, JOURNAL OF PHYSICAL CHEMISTRY B, 127, 4441-4459 (2023).

DOI: 10.1021/acs.jpcb.3c01292

Biomolecular condensates are important contributors tothe internalorganization of the cell material. While initially described as liquid-likedroplets, the term biomolecular condensates is now used to describea diversity of condensed phase assemblies with material propertiesextending from low to high viscous liquids, gels, and even glasses.Because the material properties of condensates are determined by theintrinsic behavior of their molecules, characterizing such propertiesis integral to rationalizing the molecular mechanisms that dictatetheir functions and roles in health and disease. Here, we apply andcompare three distinct computational methods to measure the viscoelasticityof biomolecular condensates in molecular simulations. These methodsare the Green-Kubo (GK) relation, the oscillatory shear (OS)technique, and the bead tracking (BT) method. We find that, althoughall of these methods provide consistent results for the viscosityof the condensates, the GK and OS techniques outperform the BT methodin terms of computational efficiency and statistical uncertainty.We thus apply the GK and OS techniques for a set of 12 different protein/RNAsystems using a sequence-dependent coarse-grained model. Our resultsreveal a strong correlation between condensate viscosity and density,as well as with protein/RNA length and the number of stickers vs spacersin the amino acid protein sequence. Moreover, we couple the GK andthe OS technique to nonequilibrium molecular dynamics simulationsthat mimic the progressive liquid-to-gel transition of protein condensatesdue to the accumulation of interprotein beta-sheets. We comparethe behavior of three different protein condensates, i.e., those formedby either hnRNPA1, FUS, or TDP-43 proteins, whose liquid-to- gel transitionsare associated with the onset of amyotrophic lateral sclerosis andfrontotemporal dementia. We find that both the GK and OS techniquessuccessfully predict the transition from functional liquid- like behaviorto kinetically arrested states once the network of interprotein beta-sheetshas percolated through the condensates. Overall, our work providesa comparison of different modeling rheological techniques to assessthe viscosity of biomolecular condensates, a critical magnitude thatprovides information on the behavior of biomolecules inside condensates.

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