RNA Folding: Conformational Statistics, Folding Kinetics, and Ion Electrostatics

Abstract

RNA folding is a remarkably complex problem that involves ion-mediated electrostatic interaction, conformational entropy, base pairing and stacking, and noncanonical interactions. During the past decade, results from a variety of experimental and theoretical studies pointed to (a) the potential ion correlation effect in Mg 2+ -RNA interactions, (b) the rugged energy landscapes and multistate RNA folding kinetics even for small RNA systems such as hairpins and pseudoknots, (c) the intraloop interactions and sequence-dependent loop free energy, and (d) the strong nonadditivity of chain entropy in RNA pseudoknot and other tertiary folds. Several related issues, which have not been thoroughly resolved, require combined approaches with thermodynamic and kinetic experiments, statistical mechanical modeling, and all-atom computer simulations.

RNA structure prediction: Progress and perspective

“…[44] Kinefold predicts the structures of pseudoknots with topological and geometrical constraints through a long-time-scale RNA folding simulation, [45] which follows the stochastic closing and opening of individual RNA helices . In addition, the thermodynamic parameters of pseudoknots loop can also be derived from a lattice model [40,47,48] and based on which, the Vfold predicts the free energy landscapes of pseudoknots. [40,48] …”

“…In addition, the thermodynamic parameters of pseudoknots loop can also be derived from a lattice model [40,47,48] and based on which, the Vfold predicts the free energy landscapes of pseudoknots. [40,48] …”

“…[48,[104][105][106] For instance, riboswitches usually perform their functions by changing structure rather than retaining a static native structure. [106] This indicates that the kinetic RNA structures that developed during the folding process can be important for RNA functions.…”

Computing the conformational entropy for RNA folds

“…First, unlike the simulation approaches, the Vfold model enables statistical mechanical calculations based on the complete ensemble of the reduced conformations. 4,9,23,27 Second, it provides a reliable lowresolution structural model, which can serve as a scaffold for further all-atom refinement through molecular dynamics computations. …”

“…This approach to the entropy and free energy for a tertiary fold is in sharp contrast to the approach for a secondary structure, where one can rely on empirical entropy and enthalpy parameters for each individual loop or base stack to predict the free energy of the whole ͑secondary͒ structure. Physics-based RNA folding theories can be classified into two types: statistical mechanical modeling [2][3][4][5][6][7][8][9] and computer simulation modeling. [10][11][12] Both types of approaches have provided useful insights into the folding mechanisms from the nucleotide sequence.…”