Understanding Base Pairing Interactions in Aqueous Environment

Base pairing plays a pivotal role in DNA functions. But while the complementarity between Watson-Crick matched bases is conventionally believed to arise from the different number of hydrogen bonds in G|C pairs versus A|T, the energetics of these hydrogen bonds are heavily renormalized by the aqueous solvent. We computationally extracted the solvent components of the free energy, entropy and enthalpy for canonical and some wobble and stacked base pairs. For all of them, the solvent's contribution to the base pairing free energy appears to be exclusively destabilizing. While the direct hydrogen bonding interactions in the G|C pair is much stronger than A|T, the thermodynamic resistance produced by the solvent also pushes back more forcefully against G|C pair formation compared to A|T, generating a difference in thermodynamic stability of only ~1 kcal/mol between them. We have profiled the density of water molecules in the solvent adjacent to the bases and observed a decrease in the solvent's entropy as a result of a "freezing" transition where waters are recruited into the gap between the bases to compensate for the unsatisfied hydrogen bonds between them.