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

[Image: see text] 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 → σ*-type charge transfer from filled π 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: ρ, (ii) its Laplacian: ∇(2)ρ, (iii) stabilization energy due to n → σ*-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.