Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition

Repeat expanded RNA molecules aggregate under certain conditions both in vitro and in vivo. Understanding the mechanism for aggregation--including how aggregation properties change with sequence and environmental conditions--would explain and predict the behavior of RNA-based biomolecular condensates, and enable the rational design of RNA-based materials. Here, we introduce an analytical framework to predict aggregation for any repeat RNA sequence, accounting for both intra- and inter-molecular bonding. By enumerating the equilibrium landscape of multimers, we reveal the driving force for aggregation: 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, and enables the design of programmable RNA condensates.