Predicting structure and stability for RNA complexes with intermolecular loop–loop base-pairing

Abstract

RNA loop-loop interactions are essential for genomic RNA dimerization and regulation of gene expression. In this article, a statistical mechanics-based computational method that predicts the structures and thermodynamic stabilities of RNA complexes with loop-loop kissing interactions is described. The method accounts for the entropy changes for the formation of loop-loop interactions, which is a notable advancement that other computational models have neglected. Benchmark tests with several experimentally validated systems show that the inclusion of the entropy parameters can indeed improve predictions for RNA complexes. Furthermore, the method can predict not only the native structures of RNA/RNA complexes but also alternative metastable structures. For instance, the model predicts that the SL1 domain of HIV-1 RNA can form two different dimer structures with similar stabilities. The prediction is consistent with experimental observation. In addition, the model predicts two different binding sites for hTR dimerization: One binding site has been experimentally proposed, and the other structure, which has a higher stability, is structurally feasible and needs further experimental validation.

On the conformational stability of the smallest RNA kissing complexes maintained through two G·C base pairs

“…This is consistent with previous studies that demonstrated the significant contributions of the loop-closing base pair to the thermal stability of loop-loop kissing interactions in various biological systems such as the kissing complex of TAR-aptamer of HIV [35–37], and the RNA I-RNA II complex of ColE1 plasmid [38, 39]. Both H2-CG and H3-CG showed drastic decrease in both thermal and mechanical stability of their kissing complexes, suggesting that the change of 5’A•U3’/5’U•A3’ to 5’C•G3’ may partially disrupt even the conformation of the 5’GACG3’ tetra-loop, making it less optimized for loop-to-loop kissing interactions.…”

Theory and Modeling of RNA Structure and Interactions with Metal Ions and Small Molecules

“…Chen et al developed a statistical mechanics-based virtual bond lattice model (“Vfold”) to compute the entropy parameters through conformation enumeration for pseudoknotted structures, kissing loops, and RNA-RNA kissing complexes (19, 20, 23, 90). …”

A Method to Predict the Structure and Stability of RNA/RNA Complexes

“…For example, during the mRNA splicing process, RNA/RNA complexes formed by small nuclear RNAs undergo multiple structural rearrangements in the different steps of splicing, 11 microRNAs regulate gene expression by binding to gene targets (at 3′ untranslated regions of target mRNA transcripts), 12 and RNA/RNA dimerization plays essential role in viral replication. 13, 14 Many of the processes of RNA-RNA binding are facilitated by the intermolecular loop-loop interactions between RNA molecules.…”

“…The results led to several predictions for RNA mechanisms, such as pseudoknot-involved conformational switch between bistable secondary structures, 26 microRNA-gene target interactions, 12 and RNA/RNA kissing dimerization in viral replication. 13, 14 …”