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Estimating Strengths of Individual Hydrogen Bonds in RNA Base Pairs: Toward a Consensus between Different Computational Approaches.

ABSTRACT: Noncoding RNA molecules are composed of a large variety of noncanonical base pairs that shape up their functionally competent folded structures. Each base pair is composed of at least two interbase hydrogen bonds (H-bonds). It is expected that the characteristic geometry and stability of different noncanonical base pairs are determined collectively by the properties of these interbase H-bonds. We have studied the ground-state electronic properties [using density functional theory (DFT) and DFT-D3-based methods] of all the 118 normal base pairs and 36 modified base pairs, belonging to 12 different geometric families (cis and trans of WW, WH, HH, WS, HS, and SS) that occur in a nonredundant set of high-resolution RNA crystal structures. Having addressed some of the limitations of the earlier approaches, we provide here a comprehensive compilation of the average energies of different types of interbase H-bonds (E _HB). We have also characterized each interbase H-bond using 13 different parameters that describe its geometry, charge distribution at its bond critical point (BCP), and n ? ?*-type charge transfer from filled ? orbitals of the H-bond acceptor to the empty antibonding orbital of the H-bond donor. On the basis of the extent of their linear correlation with the H-bonding energy, we have shortlisted five parameters to model linear equations for predicting E _HB values. They are (i) electron density at the BCP: ?, (ii) its Laplacian: ?²?, (iii) stabilization energy due to n ? ?*-type charge transfer: E(2), (iv) donor-hydrogen distance, and (v) hydrogen-acceptor distance. We have performed single variable and multivariable linear regression analysis over the normal base pairs and have modeled sets of linear relationships between these five parameters and E _HB. Performance testing of our model over the set of modified base pairs shows promising results, at least for the moderately strong H-bonds.

SUBMITTER: Halder A

PROVIDER: S-EPMC6648064 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Estimating Strengths of Individual Hydrogen Bonds in RNA Base Pairs: Toward a Consensus between Different Computational Approaches.

Halder Antarip A Data Dhruv D Seelam Preethi P PP Bhattacharyya Dhananjay D Mitra Abhijit A

ACS omega 20190423 4

Noncoding RNA molecules are composed of a large variety of noncanonical base pairs that shape up their functionally competent folded structures. Each base pair is composed of at least two interbase hydrogen bonds (H-bonds). It is expected that the characteristic geometry and stability of different noncanonical base pairs are determined collectively by the properties of these interbase H-bonds. We have studied the ground-state electronic properties [using density functional theory (DFT) and DFT-D ...[more]

PMID: 31459834

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Project description:We address the recent debate surrounding the ability of 2,4-difluorotoluene (F), a low-polarity mimic of thymine (T), to form a hydrogen-bonded complex with adenine in DNA. The hydrogen bonding ability of F has been characterized as small to zero in various experimental studies, and moderate to small in computational studies. However, recent X-ray crystallographic studies of difluorotoluene in DNA/RNA have indicated, based on interatomic distances, possible hydrogen bonding interactions between F and natural bases in nucleic acid duplexes and in a DNA polymerase active site. Since F is widely used to measure electrostatic contributions to pairing and replication, it is important to quantify the impact of this isostere on DNA stability. Here, we studied the pairing stability and selectivity of this compound and a closely related variant, dichlorotoluene deoxyriboside (L), in DNA, using both experimental and computational approaches. We measured the thermodynamics of duplex formation in three sequence contexts and with all possible pairing partners by thermal melting studies using the van't Hoff approach, and for selected cases by isothermal titration calorimetry (ITC). Experimental results showed that internal F-A pairing in DNA is destabilizing by 3.8 kcal/mol (van't Hoff, 37 °C) as compared with T-A pairing. At the end of a duplex, base-base interactions are considerably smaller; however, the net F-A interaction remains repulsive while T-A pairing is attractive. As for selectivity, F is found to be slightly selective for adenine over C, G, T by 0.5 kcal mol, as compared with thymine's selectivity of 2.4 kcal/mol. Interestingly, dichlorotoluene in DNA is slightly less destabilizing and slightly more selective than F, despite the lack of strongly electronegative fluorine atoms. Experimental data were complemented by computational results, evaluated at the M06-2X/6-31+G(d) and MP2/cc-pVTZ levels of theory. These computations suggest that the pairing energy of F to A is ~28% of that of T-A, and most of this interaction does not arise from the F···HN interaction, but rather from the CH···N interaction. The nucleobase analogue shows no inherent selectivity for adenine over other bases, and L-A pairing energies are slightly weaker than for F-A. Overall, the results are consistent with a small favorable noncovalent interaction of F with A offset by a large desolvation cost for the polar partner. We discuss the findings in light of recent structural studies and of DNA replication experiments involving these analogues.

Dataset Information

Estimating Strengths of Individual Hydrogen Bonds in RNA Base Pairs: Toward a Consensus between Different Computational Approaches.

Publications

Estimating Strengths of Individual Hydrogen Bonds in RNA Base Pairs: Toward a Consensus between Different Computational Approaches.

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