Predicting RNA pseudoknot folding thermodynamics

Based on the experimentally determined atomic coordinates for RNA helices and the self-avoiding walks of the P (phosphate) and C4 (carbon) atoms in the diamond lattice for the polynucleotide loop conformations, we derive a set of conformational entropy parameters for RNA pseudoknots. Based on the entropy parameters, we develop a folding thermodynamics model that enables us to compute the sequence-specific RNA pseudoknot folding free energy landscape and thermodynamics. The model is validated through extensive experimental tests both for the native structures and for the fold-ing thermodynamics. The model predicts strong sequence-dependent helix-loop competitions in the pseudoknot stability and the resultant confor-mational switches between different hairpin and pseudoknot structures. For instance, for the pseudo-knot domain of human telomerase RNA, a native-like and a misfolded hairpin intermediates are found to coexist on the (equilibrium) folding pathways, and the interplay between the stabilities of these inter-mediates causes the conformational switch that may underlie a human telomerase disease