Computational insight into the broad substrate specificity of enzymes that process nucleic acids

Abstract

Many enzymes that bind DNA and RNA possess broad substrate specificity and play diverse roles in biology. Three classes of enzymes with broad substrate specificity are nucleoside hydrolases that salvage nucleic acid building blocks, and alkyladenine DNA glycosylases (AAG) and AlkB enzymes, which repair alkylated and/or deaminated DNA damage. This thesis uses advanced computational techniques to examine how enzymes process structurally diverse substrates. Specifically, structural and energetic information is provided by molecular dynamics (MD) simulations, quantum mechanics (QM) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations, which provide insight into how each enzyme active site changes to accommodate unique substrates and quantify the impact that these changes have on catalyzed reactions. From these results, atomistic explanations for the activity of these enzymes is obtained, which can be used to develop new treatments for diseases. The computational approach presented can be applied to other enzymes that exhibit broad substrate specificity.