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Abstract RNA molecules aggregate under certain conditions. The resulting condensates are implicated in human neurological disorders, and can potentially be designed towards specified bulk properties in vitro. However, the mechanism for aggregation—including how aggregation properties change with sequence and environmental conditions—remains poorly understood. To address this challenge, we introduce an analytical framework based on multimer enumeration. Our approach reveals the driving force for aggregation to be the increased configurational entropy associated with the multiplicity of ways to form bonds in the aggregate. Our model uncovers rich phase behavior, including a sequence-dependent reentrant phase transition, and repeat parity-dependent aggregation. We validate our results by comparison to a complete computational enumeration of the landscape, and to previously published molecular dynamics simulations. Our work unifies and extends published results, both explaining the behavior of CAG-repeat RNA aggregates implicated in Huntington’s disease, and enabling the rational design of programmable RNA condensates.
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Sequence complexity and monomer rigidity control the morphologies and aging dynamics of protein aggregates
Understanding the biophysical basis of protein aggregation is important in biology because of the potential link to several misfolding diseases. Although experiments have shown that protein aggregates adopt a variety of morphologies, the dynamics of their formation are less well characterized. Here, we introduce a minimal model to explore the dependence of the aggregation dynamics on the structural and sequence features of the monomers. Using simulations, we demonstrate that sequence complexity (codified in terms of word entropy) and monomer rigidity profoundly influence the dynamics and morphology of the aggregates. Flexible monomers with low sequence complexity (corresponding to repeat sequences) form liquid-like droplets that exhibit ergodic behavior. Strikingly, these aggregates abruptly transition to more ordered structures, reminiscent of amyloid fibrils, when the monomer rigidity is increased. In contrast, aggregates resulting from monomers with high sequence complexity are amorphous and display nonergodic glassy dynamics. The heterogeneous dynamics of the low and high-complexity sequences follow stretched exponential kinetics, which is one of the characteristics of glassy dynamics. Importantly, at nonzero values of the bending rigidities, the aggregates age with the relaxation times that increase with the waiting time. Informed by these findings, we provide insights into aging dynamics in protein condensates and contrast the behavior with the dynamics expected in RNA repeat sequences. Our findings underscore the influence of the monomer characteristics in shaping the morphology and dynamics of protein aggregates, thus providing a foundation for deciphering the general rules governing the behavior of protein condensates.
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- Award ID(s):
- 2320256
- PAR ID:
- 10558955
- Publisher / Repository:
- Proceedings of the National Academy of Sciences
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 121
- Issue:
- 50
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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