Stacking interactions involving non-Watson-Crick basepairs: dispersion corrected density functional theory studies

Area of Science:

• * Molecular Biology
• * Biophysics
• * Computational Chemistry

Background:

• * The G:A (guanine:adenine) base pair, stabilized by sugar-Hoogsteen hydrogen bonds in a trans orientation (G:A S:HT), is frequently observed and highly stable in solved RNA structures.
• * Understanding the structural and energetic basis of non-Watson-Crick base pairs is crucial for predicting RNA folding and function.

Purpose of the Study:

• * To investigate the stacking energy of RNA sequences containing the G:A S:HT base pair using Density Functional Theory with Dispersion correction (DFT-D).
• * To determine the most stable conformations of G:A S:HT containing sequences by exploring base pair orientation parameters.
• * To assess the impact of sugar-phosphate backbone connectivity on the stability and predicted structures of these RNA sequences.

Main Methods:

• * Stacking energy analysis of two specific RNA sequences (C:G W:WC::G:A S:HT and G:C W:WC::G:A S:HT) using DFT-D.
• * Comprehensive scanning of base pair orientation parameters to identify energetically favorable conformations.
• * Incorporation of a coarse-grained energy term representing sugar-phosphate backbone connectivity.

Main Results:

• * The most stable conformations for the studied sequences were found to deviate significantly from the orientations most commonly observed in experimental structures.
• * Including backbone connectivity energy alongside DFT-D stacking energies resulted in predicted structures closely matching experimentally determined ones.
• * Optimal stacking was associated with low twist, positive roll, and negative slide parameters, aligning with typical A-RNA structural features.

Conclusions:

• * The study highlights that the most stable conformations of G:A S:HT containing RNA sequences may not be the most frequently observed ones.
• * Integrating backbone flexibility significantly improves the accuracy of computational predictions for RNA structures.
• * The C:G W:WC::G:A S:HT sequence exhibits greater stacking stability than G:C W:WC::G:A S:HT, likely due to superior base stacking overlap.