Many enzymes control the chemistry and biology of modified nucleic acids in cells. For example, DNA modifications arising as damage must be repaired or bypassed for cell survival. Alternatively, enzymes introduce or remove DNA modifications as part of epigenetic regulation or generate modification cascades to impart diverse RNA structures and functions. These biomolecular machines can also be harnessed in medicine and nanotechnology. For example, understanding the function of natural enzymes can inspire the engineering of new proteins to facilitate the production of novel nucleic acid-based biomaterials, while understanding how DNA damage evades repair or bypass can assist developing cancer treatments with greater efficacy. However, critical information about molecular reactions (transition structures, barrier heights) is difficult to obtain from experiments at least in part because key species along reaction pathways are short lived. Indeed, most currently available mechanistic information for enzymes that process nucleic acids has been conjectured from crystal structures or mutagenesis experiments. Therefore, computational chemistry has a unique role to play in characterizing the molecular details of enzyme catalyzed reactions that form and break bonds at modification sites, between nucleobases and sugars (glycosidic bonds), and within phosphodiester backbones, which form the basis of modified nucleic acid chemistry.

With this goal in mind, research in the Wetmore group uses a multipronged computational approach to understand important cellular reactions. Specifically, molecular dynamics (MD) simulations are used to provide information about nucleic acid structure and how repair enzymes bind to a range of modified nucleic acid substrates. Subsequently, combined quantum mechanics–molecular mechanics (QM/MM) methods are used to uncover the details of the catalytic mechanisms. This talk will provide a survey of some of the recent topics of interest in the Wetmore lab related to the enzymatic processing of nucleic acids. The information uncovered is vital for the future design of highly selective and potent small molecule inhibitors for disease management and the design of new enzymes that can process modified nucleic acids as biotechnological tools.