Salt-dependent self-association of trinucleotide repeat RNA sequences

Abstract

Low complexity repeat RNA sequences self-associate by homotypic interactions to form condensates. Using simulations of a coarse grained Single-Interaction Site model for (CAG)n(n= 30 and 31), we show that the salt-dependent free energy gap, ∆GS, between the ground (perfect hairpin) and the excited state (slipped hairpin (SH) with one CAG overhang) of monomer (neven) is the primary factor that determines the rates and yield of self-assembly. For oddn, the SH ground state free energy (GS) is used to predict self-association kinetics. As the monovalent salt concentration,CS, increases ∆GSandGSincreases, which in turn decreases the self-association rates. In contrast, ∆GSfor scrambled sequences, with the same length and sequence composition as (CAG)31but with higher complexity, is larger which greatly suppresses the propensities to aggregate. Although demonstrated explicitly for (CAG)30and (CAG)31polymers, the finding that there is an inverse correlation betweenCS-dependent ∆GSorGSand RNA aggregation is general. Our predictions are amenable to experimental tests.