A Deep Dive into DNA Base Pairing Interactions Under Water

Base pairing plays a pivotal role in DNA functions and replication fidelity. But while the complementarity between Watson-Crick matched bases is generally believed to arise from the different number of hydrogen bonds in G vertical bar C pairs versus A vertical bar T, the energetics of these interactions are heavily renormalized by the aqueous solvent. Employing large-scale Monte Carlo simulations, we have extracted the solvent contribution to the free energy for canonical and some noncanonical and stacked base pairs. For all of them, the solvent's contribution to the base pairing free energy is exclusively destabilizing. While the direct hydrogen bonding interactions in the G|C pair is much stronger than A vertical bar T, the thermodynamic resistance produced by the solvent also pushes back much stronger against G vertical bar C compared to A vertical bar T, generating an only similar to 1 kcal/mol free energy difference between them. We have profiled the density of water molecules in the solvent adjacent to the bases and observed a "freezing" behavior where waters are recruited into the gap between the bases to compensate for the unsatisfied hydrogen bonds between them. A very small number of water molecules that are associated with the Watson-Crick donor/acceptor atoms turn out to be responsible for the majority of the solvent's thermodynamic resistance to base pairing. The absence or presence of these near-field waters can be used to enhance fidelity during DNA replication.