Hydrogen Bonding in Natural and Unnatural Base Pairs-A Local Vibrational Mode Study

In this work hydrogen bonding in a diverse set of 36 unnatural and the three natural Watson Crick base pairs adenine (A)-thymine (T), adenine (A)-uracil (U) and guanine (G)-cytosine (C) was assessed utilizing local vibrational force constants derived from the local mode analysis, originally introduced by Konkoli and Cremer as a unique bond strength measure based on vibrational spectroscopy. The local mode analysis was complemented by the topological analysis of the electronic density and the natural bond orbital analysis. The most interesting findings of our study are that (i) hydrogen bonding in Watson Crick base pairs is not exceptionally strong and (ii) the N-HMIDLINE HORIZONTAL ELLIPSISN is the most favorable hydrogen bond in both unnatural and natural base pairs while O-HMIDLINE HORIZONTAL ELLIPSISN/O bonds are the less favorable in unnatural base pairs and not found at all in natural base pairs. In addition, the important role of non-classical C-HMIDLINE HORIZONTAL ELLIPSISN/O bonds for the stabilization of base pairs was revealed, especially the role of C-HMIDLINE HORIZONTAL ELLIPSISO bonds in Watson Crick base pairs. Hydrogen bonding in Watson Crick base pairs modeled in the DNA via a QM/MM approach showed that the DNA environment increases the strength of the central N-HMIDLINE HORIZONTAL ELLIPSISN bond and the C-HMIDLINE HORIZONTAL ELLIPSISO bonds, and at the same time decreases the strength of the N-HMIDLINE HORIZONTAL ELLIPSISO bond. However, the general trends observed in the gas phase calculations remain unchanged. The new methodology presented and tested in this work provides the bioengineering community with an efficient design tool to assess and predict the type and strength of hydrogen bonding in artificial base pairs.

Automated summary

The study found that hydrogen bonding in Watson-Crick base pairs is not exceptionally strong, with N-H···N being the most favorable hydrogen bond type. Non-classical C-H···O bonds play an important role in stabilizing base pairs. The DNA environment influences the strength of hydrogen bonds, but trends observed in gas phase calculations remain unchanged.