Biomolecular condensates are important contributors to
the internal
organization of the cell material. While initially described as liquid-like
droplets, the term biomolecular condensates is now used to describe
a diversity of condensed phase assemblies with material properties
extending from low to high viscous liquids, gels, and even glasses.
Because the material properties of condensates are determined by the
intrinsic behavior of their molecules, characterizing such properties
is integral to rationalizing the molecular mechanisms that dictate
their functions and roles in health and disease. Here, we apply and
compare three distinct computational methods to measure the viscoelasticity
of biomolecular condensates in molecular simulations. These methods
are the Green–Kubo (GK) relation, the oscillatory shear (OS)
technique, and the bead tracking (BT) method. We find that, although
all of these methods provide consistent results for the viscosity
of the condensates, the GK and OS techniques outperform the BT method
in terms of computational efficiency and statistical uncertainty.
We thus apply the GK and OS techniques for a set of 12 different protein/RNA
systems using a sequence-dependent coarse-grained model. Our results
reveal a strong correlation between condensate viscosity and density,
as well as with protein/RNA length and the number of stickers vs spacers
in the amino acid protein sequence. Moreover, we couple the GK and
the OS technique to nonequilibrium molecular dynamics simulations
that mimic the progressive liquid-to-gel transition of protein condensates
due to the accumulation of interprotein β-sheets. We compare
the behavior of three different protein condensates, i.e., those formed
by either hnRNPA1, FUS, or TDP-43 proteins, whose liquid-to-gel transitions
are associated with the onset of amyotrophic lateral sclerosis and
frontotemporal dementia. We find that both the GK and OS techniques
successfully predict the transition from functional liquid-like behavior
to kinetically arrested states once the network of interprotein β-sheets
has percolated through the condensates. Overall, our work provides
a comparison of different modeling rheological techniques to assess
the viscosity of biomolecular condensates, a critical magnitude that
provides information on the behavior of biomolecules inside condensates.