Theory of RNA Folding: From Hairpins to Ribozymes

The rugged nature of the RNA folding landscape is determined by a number of conflicting interactions like repulsive electrostatic potential between the charges on the phosphate groups, constraints due to loop entropy, base stacking, and hydrogen bonding that operate on various length scales. As a result the kinetics of self-assembly of RNA is complex, but can be easily modulated by varying the concentrations, sizes, and shapes of the counterions. Here, we provide a theoretical description of RNA folding that is rooted in the energy landscape perspective and polyelectrolyte theory. A consequence of the rugged folding landscape is that, self-assembly of RNA into compact three-dimensional structures occurs by parallel routes, and is best described by the kinetic partitioning mechanism (KPM). According to KPM one fraction of molecules (Φ) folds rapidly while the remaining gets trapped in one of several competing basins of attraction. The partition factor Φ can be altered by point mutations as well as by changing the initial conditions such as ion concentration, size and valence of ions. We show that even hairpin formation, either by temperature or force quench, captures much of the features of folding of large RNA molecules. Despite the complexity of the folding process, we show that the KPM concepts from polyelectrolyte theory, and charge density of ions can be used to explain the stability, pathways and their diversity, and the plasticity of the transition state ensemble of RNA self-assembly.