EARLY EVENTS IN RNA FOLDING

Abstract

We describe a conceptual framework for understanding the way large RNA molecules fold based on the notion that their free-energy landscape is rugged. A key prediction of our theory is that RNA folding can be described by the kinetic partitioning mechanism (KPM). According to KPM a small fraction of molecules folds rapidly to the native state whereas the remaining fraction is kinetically trapped in a low free-energy non-native state. This model provides a unified description of the way RNA and proteins fold. Single-molecule experiments on Tetrahymena ribozyme, which directly validate our theory, are analyzed using KPM. We also describe the earliest events that occur on microsecond time scales in RNA folding. These must involve collapse of RNA molecules that are mediated by counterion-condensation. Estimates of time scales for the initial events in RNA folding are provided for the Tetrahymena ribozyme.

Unwinding RNA's secrets: advances in the biology, physics, and modeling of complex RNAs

“…Large catalytic RNAs such as the group I intron from Tetrahymena thermophila and the RNase P RNA from Bacillus subtilis fold at vastly different rates under different conditions upon addition of Mg 2+ and have been shown to fold via multiple parallel pathways, in which different molecules follow different routes with different rates and intermediates, to a common final folded structure [4,5]. These observations support the common view that RNAs traverse rugged energy landscapes as they fold [6,7]. However, little is known about the true shape of these…”

Understanding looping kinetics of a long polymer molecule in solution. Exact solution for delta function sink model

“…Loop formation is believed to be an initial step in understanding several protein [4,12] and RNA folding [13] events. The theories of loop formation dynamics are in general approximate [5,7].…”

Assembly of core helices and rapid tertiary folding of a small bacterial group I ribozyme

“…Recent work has outlined the Mg 2ϩ -dependent folding pathways of large ribozymes (1,2). Experimental and theoretical results suggest that the initial association of divalent cations induces collapse of the extended RNA chain into more compact structures that favor formation of tertiary interactions (3)(4)(5)(6)(7)(8). The structure of the compact intermediates and the extent to which these interactions lead to the native conformation are not yet characterized.…”

“…Many larger RNAs, such as the Tetrahymena group I and Bacillus subtilis RNase P ribozymes, fold slowly in vitro because a large fraction of the RNA population becomes trapped in misfolded intermediates (11,12). An important question is whether RNAs with a simpler 3D architecture are more likely to fold directly to the native structure, as expected from theoretical models (4). Furthermore, we want to know whether the likelihood of misfolding can be predicted from the specificity of counterion-induced collapse.…”