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WIREs Comput Mol Sci
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Computational studies of DNA repair: Insights into the function of monofunctional DNA glycosylases in the base excision repair pathway

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Abstract The information contained within DNA as a sequence of nucleobases is required for life of most organisms, yet can get altered when the nucleobases are damaged upon exposure to many internal (hormones) and external (ultraviolet sunlight, pollutants) sources. As a result, repair pathways exist to combat the potentially detrimental effects of DNA damage. Nonbulky nucleobase damage (nucleobase oxidation, alkylation and deamination) is commonly removed by the base excision repair (BER) pathway, which involves several enzymes. The first BER enzymes are the DNA glycosylases, which are responsible for identifying the damaged base, flipping the base into the enzyme active site and removing the damaged nucleobase from the sugar–phosphate backbone. Due to the stability of many forms of damaged DNA, the DNA glycosylases must achieve great catalytic power. Understanding the mechanistic details associated with DNA glycosylases is essential for developing detection and treatment strategies for many diseases as abnormal glycosylase function has been associated with cancers, metabolic dysfunctions, neurodegeneration and epigenetic programming during embryo development. Molecular level insight into the function of a wide range of DNA glycosylases has been obtained from computational chemistry, including quantum mechanical cluster calculations, combined quantum mechanics‐molecular mechanics approaches and molecular dynamics simulations. By discussing some of the modeling that has been performed to date on monofunctional DNA glycosylases, the key contributions of the field of computational chemistry to broadening our understanding of the function of this important enzyme family, as well as the critical interplay between traditional biochemical experiments and computer calculations, is highlighted. This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis Structure and Mechanism > Computational Biochemistry and Biophysics Electronic Structure Theory > Combined QM/MM Methods
(a) The general base excision repair (BER) process, depicting the fundamental roles of (monofunctional) DNA glycosylases in identifying the damaged base among canonical bases (shown as colored pieces) and breaking the bond between the damaged base and the sugar–phosphate backbone (shown as black). (b) Chemical structure and numbering of canonical DNA nucleobases, as well as representative damaged products that are repaired by monofunctional DNA glycosylases
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(a) Proposed alkyladenine DNA glycosylase (AAG) mechanism of action based on combined experimental and computational studies as described in the main text. Crystal structure of AAG bound to DNA containing (b) εA (PDB ID, 1EWN) or (c) εC (PDB ID: 3QI5)
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(a) Crystal structure of thymine DNA glycosylase (TDG) (PDB ID: 5T2W). (b) Proposed mechanism of action of TDG for the excision of fmC
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Proposed mechanisms of action of MutY, involving (a) Glu43 acting as the general acid and base as predicted by the lesion recognition complex (LRC) crystal structure and kinetic isotope effects, (b) Glu43 acting as the general acid and the departed monoprotonated A as the general base as predicted by CPMD calculations, (c) Glu43 acting as the general acid and Asp144 acting as the general base as hypothesized based on the fluorinated lesion recognition complex (FLRC) crystal structure and ONIOM(QM:QM) calculations, and (d) the formation of a DNA–protein crosslink through Asp144 as predicted based on the TSAC crystal structure
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Available crystal structures for MutY, including (a) the lesion recognition complex (LRC, PDB ID: 1RRQ), (b) the fluorinated lesion recognition complex (FLRC, PDB ID: 3G0Q), and (c) the transition state analog complex (TSAC, PDB ID: 5DPK)
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(a) Crystal structure of uracil DNA glycosylase (UDG) bound to an inhibitor (pseudouridine; PDB ID: 1EMH). (b) Initial proposed mechanism for UDG based on experimental data with Asp145 acting as the general base. (c) Newest proposed mechanism for UDG based on computational work with His148 acting as the general base
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Electronic Structure Theory > Combined QM/MM Methods
Structure and Mechanism > Computational Biochemistry and Biophysics
Structure and Mechanism > Reaction Mechanisms and Catalysis

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