Abstract
The G:C reverse Watson–Crick (W:W trans) base pair, also known as Levitt base pair in the context of tRNAs, is a structurally and functionally important base pair that contributes to tertiary interactions joining distant domains in functional RNA molecules and also participates in metabolite binding in riboswitches. We previously indicated that the isolated G:C W:W trans base pair is a rather unstable geometry, and that dicationic metal binding to the Guanine base or posttranscriptional modification of the Guanine can increase its stability. Herein, we extend our survey and report on other H-bonding interactions that can increase the stability of this base pair. To this aim, we performed a bioinformatics search of the PDB to locate all the occurencies of G:C trans base pairs. Interestingly, 66% of the G:C trans base pairs in the PDB are engaged in additional H-bonding interactions with other bases, the RNA backbone or structured water molecules. High level quantum mechanical calculations on a data set of representative crystal structures were performed to shed light on the structural stability and energetics of the various crystallographic motifs. This analysis was extended to the binding of the preQ1 metabolite to a preQ1-II riboswitch.
Highlights
RNA molecules fold giving rise to complex structures that exhibit evolutionary conserved architectures
We have previously shown that the binding of a divalent metal ion to the N7 atom of the guanine, or the archaeosine (7-formamidino-7deazaguanosine) posttranscriptional modification [36], acting as a ‘covalent mimic’ of the metal binding to the N7 atom, can stabilize the G:C W:W trans geometry in the context of the tRNA structure [12]
The quantum mechanics (QM) approach adopted here has been thoroughly validated in the study of the structure and energetics of H-bonded bases in several nucleic acid systems [11,20,21,22,38,39,40,41,42,43,44]. Using this knowledge, we decompose the binding of the preQ1 metabolite by the Lactobacillus rhamnosus class II preQ1 riboswitch [35]. Based on this approach, combining structural bioinformatics and accurate QM calculations, we address the following fundamental questions: (i) how many types of higher order structures involving G:C W:W trans base pair as a core motif are present in RNA 3D structures; (ii) how the formation of higher order structures influences the geometric stability of the G:C W:W trans pair; (iii) what are the other environmental factors that provide H-bonding interactions that may affect the geometric stability of G:C W:W trans pairs in RNA structures
Summary
RNA molecules fold giving rise to complex structures that exhibit evolutionary conserved architectures. Quantum mechanics (QM)-based approaches revealed fundamental in the accurate characterization of small structural units, such as simple H-bonded base pairs, which are otherwise difficult to characterize experimentally This approach has been possible because, in the large majority of the cases, the gas phase optimization of isolated pairs results in a geometry that is consistent with the experimental one, reflecting the intrinsic geometrical stability of the base pairing interaction and allowing to use these methods to quantify the energetics of the interaction [11,16,21,22,23,24,25,26,27,28]. On this basis, when a large discrepancy occurs between the calculated geometry of a base pair and the geometry of the same base pair in experimental structures, this evidence has been taken as an indication that other effects contribute to the stability of the specific base pair geometry in the experimental structure
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