Structure folding of RNA kissing complexes in salt solutions: predicting 3D structure, stability, and folding pathway

Abstract

RNA kissing complexes are essential for genomic RNA dimerization and regulation of gene expression, and their structures and stability are critical to their biological functions. In this work, we used our previously developed coarse-grained model with an implicit structure-based electrostatic potential to predict three-dimensional (3D) structures and stability of RNA kissing complexes in salt solutions. For extensive RNA kissing complexes, our model shows great reliability in predicting 3D structures from their sequences, and our additional predictions indicate that the model can capture the dependence of 3D structures of RNA kissing complexes on monovalent/divalent ion concentrations. Moreover, the comparisons with extensive experimental data show that the model can make reliable predictions on the stability for various RNA kissing complexes over wide ranges of monovalent/divalent ion concentrations. Notably, for RNA kissing complexes, our further analyses show the important contribution of coaxial stacking to the 3D structures and stronger stability than the corresponding kissing-interface duplexes at high salts. Furthermore, our comprehensive analyses for RNA kissing complexes reveal that the thermally folding pathway for a complex sequence is mainly determined by the relative stability of two possible folded states of kissing complex and extended duplex, which can be significantly modulated by its sequence.

Salt-Dependent RNA Pseudoknot Stability: Effect of Spatial Confinement

“…To predict the 3D structures and stability of RNAs in various ion solutions, we have developed a new CG model with involving the effects of ions (Shi et al, 2014a(Shi et al, , 2015(Shi et al, , 2018Jin et al, 2018Jin et al, , 2019. In the model, each nucleotide is represented by three beads, which represent the three atom groups: phosphate group (P), sugar ring (C), and base (N), respectively.…”

“…The last term U el in Equation ( 1) is an electrostatic potential corresponding to electrostatic interactions between phosphate groups (a charge of -e for each P bead at its center), which are ignored by most existing predictive models for RNA 3D structures (Hajdin et al, 2010;Rose et al, 2011;Shi et al, 2014b;Schlick and Pyle, 2017). The U el is taken into account through the combination of the Debye-Hückel approximation, the concept of counterion condensation (CC) (Manning, 1978), and the tightly bound ion (TBI) model (Tan and Chen, 2007, and the potential can well-capture the contribution of monovalent/divalent ions to RNA 3D structures (Shi et al, 2015;Jin et al, 2019).…”

“…Most of these models/methods are primarily designed to predict folded structures and cannot predict the stability of RNAs, especially in ion solutions (Shi et al, 2014b;Dawson et al, 2016;Schlick and Pyle, 2017), whereas the structural stability of RNAs can be very sensitive to ion conditions due to their polyanionic nature (Das et al, 2005;Draper et al, 2005;Chen, 2007, 2011;Qiu et al, 2010;Lipfert et al, 2014;Wang et al, 2018Meng et al, 2020). Recently, to predict the 3D structures, stability, and flexibility of RNAs in ion solutions from sequences, we have developed a new coarse-grained (CG) model, and the model has been validated for extensive RNA hairpins, kissing complex, and pseudoknots over a wide range of monovalent/divalent ion concentrations (Shi et al, 2014a(Shi et al, , 2015(Shi et al, , 2018Jin et al, 2018Jin et al, , 2019.…”

RNA 3D Structure Prediction Using Coarse-Grained Models

“…Fyta et al has developed a four-bead CG model for double-stranded RNA which uses density functional theory to determine the parameters in energy functions and can reproduce the structural and mechanical properties (Cruz-León et al, 2018). Tan et al managed to predict the 3D structures and stability of RNA kissing complexes in monovalent/divalent ion solutions by using a 3-bead CG model (Jin et al, 2019). Even for the large ribosome system, a 1-bead CG model for RNAs and proteins has been applied to study its dynamics (Trylska et al, 2005).…”

Salt effect on thermodynamics and kinetics of a single RNA base pair

“…For example, thermodynamic and single-molecule measurements have both shown that an increase in salt concentration would apparently enhance the stability of secondary segments, and a logarithm salt-dependence of the folding free energy/entropy has been empirically derived at relatively high salt concentration (e.g., between ∼0.1-1 M) (SantaLucia 1998;SantaLucia and Hicks 2004). In parallel, the influence of metal ions on the tertiary structure of RNA has been explored extensively (Woodson 2005;Draper et al 2005;Koculi et al 2007;Draper 2008;Tan and Chen 2011;Kim and Shapiro 2013;Li 2013;Wang et al 2015;Wang and Xiao 2016;Shi et al 2018;Xi et al 2018;Hori et al 2019;Jin et al 2019). For example, Li (2013) studied the role of diffuse metal ions in stabilizing a 2-bp kissing complex by single-molecule techniques and found the significant contribution of diffuse cations to the stability of tertiary interaction.…”