Occurrences of protonated base triples in RNA are determined by their cooperative binding energies and specific functional requirements

Abstract

With wide ranging diversity in their geometries, binding strengths and chemical properties, noncanonical base pairs are equipped to intricately regulate and control the structural dynamics of RNA molecules. Protonation of nucleobases adds to the diversity. Compared to the unprotonated scenario, on one hand they open up new alternatives for base pairing interactions (Class I) while on the other, they modulate the geometry and stability of existing base pairing interactions (Class II). In both cases, compensation of the energetic cost associated with nucleobase protonation at physiological pH, can be understood in terms of protonation induced restructuring of charge distribution. This not only leads to modifications in existing base-base interactions but often also leads to additional stabilizing interactions, resulting in the formation of protonated base triples. Here we report our detailed quantum chemical studies, in conjunction with structural bioinformatics based analysis of RNA crystal and NMR structure datasets, probing into the contribution of such protonated triples in the structural dynamics of RNA. Our studies revealed more than 55 varieties of protonated triples in RNA, some of which occur recurrently within conserved structural motifs present in rRNAs, tRNAs and in other synthetic RNAs. Our studies suggest that high occurrence frequencies are associated with protonated triples which satisfy the specific structural requirements of conserved motifs where they occur. For example, protonated triples with flexible geometries are involved in the formation of tertiary contacts between different distant motifs. Stabilization of protonated base pairs, through the induction of additional energetically cooperative interactions, appears to be another factor. These results provide significant insights into the sequence-structure-function relationships in RNA.

Guanidinium–amino acid hydrogen-bonding interactions in protein crystal structures: implications for guanidinium-induced protein denaturation

“…57,58 We chose oB97X-D, since it is an improved, range-separated version of the Becke's original 97 functional 59 that includes both long range correction to the non-Coulomb part of exchange functional and second order dispersion correction, and has been used in a previous similar study on biologically-relevant hydrogen-bonded complexes. 60 Furthermore, a benchmarking of the performance of DFT functionals for studying the optimized geometry, stability and cooperativity of DNA triplexes has shown that the results of the parent B97-D functional are consistent with higher theoretical levels. 61 The dispersion correction within the oB97X-D was implemented using the Grimme's 'DFT-D2' model, 62 albeit with a different damping function and unscaled dispersion correction to model the correct asymptotic pairwise vdW potentials.…”