Abstract
Unlike structures of double stranded DNA, stabilized by canonical base pairings, single stranded RNA molecules are known to fold into complex functional 3D structures. Several of these structures provide sites for binding with cognate molecules that induce conformational changes related to their respective functionalities. Their structures and functional dynamics are scripted by a multitude of noncovalent interactions, involving base edges, 2’-OH of ribose, backbone phosphates and metal cations. In the context of the importance of the ribosome as a potential drug target [1], we have studied the geometries and interaction energies associated with hydrogen bonded base pairs and pseudo pairs observed in crystal structures of drug molecules complexed with their target RNAs. Previous studies, as reviewed recently [2], provide insights into the structural aspects of these RNA-ligand interactions. However, the molecular level understanding of their role in RNA functions require the analysis of their stabilities and interaction energies. We have shown earlier how appropriate quantum chemical calculations can be used to assess gas phase interaction energies and intrinsic stabilities of nucleic acid base pairs [3 – 9]. Here we report results of our calculations, at B3LYP/6-31G(d,p) and RIMP2/aug-cc-pVDZ level, for geometry optimization and interaction energy calculation respectively, for base pairs and pseudobase pairs observed in experimental structures of distinct classes of drug molecules such as aminoglycosides, oxazolidinones, tetracyclines, lincosamides etc., bound to RNA. Our studies show that on full geometry optimization, these base pairs tend to achieve greater stability compared to that in their respective experimental geometries. The increase in interaction energies is not due to any increase in the number of hydrogen bonds but due to increase in their strengths because of increased planarity and by approaching in-range donor-acceptor distances of hydrogen bonds. Their gas phase interaction energies range from -11.32 to -29.70 kcal/mol and compare well with those of standard Watson Crick base pairs. Except for the Puromycin - Guanine pair involving sugar-sugar interaction, the Hartree Fock component dominates the interaction energies, in all fully optimised geometries, with values ranging from 53.09% to 87.13%. The EDFT-D energies ranging from -9.68 to -66.94 kcal/mol, suggest that the interaction between the RNA-Drug pairs is further stabilised due to dispersion. We also report detailed studies on the discriminative ability of the theophylline aptamer with respect to its cognate ligand. Unlike in the context of purine riboswitches observed earlier [6], cooperativity is found to be negligible in multiple base-ligand interactions studied in case of Theophylline interacting with its aptamer. However, the binding affinities of theophylline, caffeine and theobromine with the theophylline aptamer correlates well with the experimental data [10] with high binding affinity for theophylline and least for caffeine