A Deep Dive into DNA Base Pairing Interactions Under Water [article]

Rongpeng Li, Chi H. Mak
2020 bioRxiv   pre-print
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|C pairs versus A|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.
more » ... cked 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|T, the thermodynamic resistance produced by the solvent also pushes back much stronger against G|C compared to A|T, generating an only ~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 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.
doi:10.1101/2020.06.04.134981 fatcat:5nttaxl4qbckzpes346dfthkve