Structure and Energy of Non-Canonical Basepairs: Comparison of Various Computational Chemistry Methods with Crystallographic Ensembles

Abstract

Different types of non-canonical basepairs, in addition to the Watson-Crick ones, are observed quite frequently in RNA. Their importance in the three dimensional structure is not fully understood, but their various roles have been proposed by different groups. We have analyzed the energetics and geometry of 32 most frequently observed basepairs in the functional RNA crystal structures using different popular empirical, semi-empirical and ab initio quantum chemical methods and compared their optimized geometry with the crystal data. These basepairs are classified into three categories: polar, non-polar and sugar-mediated, depending on the types of atoms involved in hydrogen bonding. In case of polar basepairs, most of the methods give rise to optimized structures close to their initial geometry. The interaction energies also follow similar trends, with the polar ones having more attractive interaction energies. Some of the C-H...O/N hydrogen bond mediated non-polar basepairs are also found to be significantly stable in terms of their interaction energy values. Few polar basepairs, having amino or carboxyl groups not hydrogen bonded to anything, such as G:G H:W C, show large flexibility. Most of the non-polar basepairs, except A:G s:s T and A:G w:s C, are found to be stable; indicating C-H...O/N interaction also plays a prominent role in stabilizing the basepairs. The sugar mediated basepairs show variability in their structures, due to the involvement of flexible ribose sugar. These presumably indicate that the most of the polar basepairs along with few non-polar ones act as seed for RNA folding while few may act as some conformational switch in the RNA.

A comparison of four different conformations adopted by human telomeric G‐quadruplex using computer simulations

“…The G:G H:W C base pair is an integral part of the G‐quartet, which was studied earlier in the context of non‐canonical base pairing in RNA . In telomere, however, four such base pairs form a cyclic orientation, mostly along with a cation.…”

“…This indicated deformation of the hydrogen bond geometry holding the four guanine bases as a quartet possibly due to electrostatic repulsion between the four O6 atoms. A G:G H:W C base pair from RNA was also seen to adopt a drastically different geometry on free optimizations by few quantum chemical methods . All these facts pointed to the necessity of presence of a cation, a ligand, or some topological strain from loop or bead formation in the G‐quartets for their stability and planarity.…”

Stacking geometry for non‐canonical G:U wobble base pair containing dinucleotide sequences in RNA: dispersion‐corrected DFT‐D study

“…The optimum value of shear (2.25 Å) was obtained by varying the shear value in generated base pairs by NUCGEN and locating the most favorable hydrogen bonds. We have therefore generated 605 modeled dinucleotide structures for each dinucleotide sequence using above parameters, where the sugar‐phosphate backbone is replaced by methyl group as in normal practice …”

“…Large number of quantum chemical studies on different types of canonical and non‐canonical base pairs were done to characterize their structure and stability using various quantum chemical methods . These studies indicate that many of these non‐canonical base pairs are as stable as the canonical ones.…”

“…It was seen that unconstrained optimized structures of many of these base pairs are highly planar, indicating their ability to stack on top of another planar base pair to form double helix. Some of these, however, adopt non‐planar geometry or adopt optimized structure with drastically different hydrogen bonding scheme involving other edges of the bases . The G:U base pair, however, is seen to maintain its planar geometry with two strong N‐H…O hydrogen bonds upon geometry optimization by different ab initio quantum chemical methods.…”