Generalized Iterative Annealing Model for the action of RNA chaperones

TL;DR

This paper develops a generalized iterative annealing model to describe how RNA chaperones assist in folding by destabilizing misfolded structures or actively remodeling RNA, improving native state yield.

Contribution

It introduces passive and active kinetic models for RNA chaperone action, incorporating recent experimental findings and providing a unified theoretical framework.

Findings

Passive model effectively lowers folding barriers via transient interactions.

Active model uses ATP hydrolysis to enhance native state formation.

Native state does not reach 100% probability in steady state.

Abstract

As a consequence of the rugged landscape of RNA molecules their folding is described by the kinetic partitioning mechanism according to which only a small fraction ($\phi_F$) reaches the folded state while the remaining fraction of molecules is kinetically trapped in misfolded intermediates. The transition from the misfolded states to the native state can far exceed biologically relevant time. Thus, RNA folding in vivo is often aided by protein cofactors, called RNA chaperones, that can rescue RNAs from a multitude of misfolded structures. We consider two models, based on chemical kinetics and chemical master equation, for describing assisted folding. In the passive model, applicable for class I substrates, transient interactions of misfolded structures with RNA chaperones alone are sufficient to destabilize the misfolded structures, thus entropically lowering the barrier to folding. For this mechanism to be efficient the intermediate ribonucleoprotein (RNP) complex between collapsed RNA and protein cofactor should have optimal stability. We also introduce an active model (suitable for stringent substrates with small $\phi_F$), which accounts for the recent experimental findings on the action of CYT-19 on the group I intron ribozyme, showing that RNA chaperones does not discriminate between the misfolded and the native states. In the active model, the RNA chaperone system utilizes chemical energy of ATP hydrolysis to repeatedly bind and release misfolded and folded RNAs, resulting in substantial increase of yield of the native state. The theory outlined here shows, in accord with experiments, that in the steady state the native state does not form with unit probability.