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Molecules 2016, 21(7), 822; doi:10.3390/molecules21070822

Computational Evaluation of Nucleotide Insertion Opposite Expanded and Widened DNA by the Translesion Synthesis Polymerase Dpo4

Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge Alberta, AB T1K 3M4, Canada
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Academic Editors: James W. Gauld and Leif A. Eriksson
Received: 16 May 2016 / Revised: 8 June 2016 / Accepted: 14 June 2016 / Published: 23 June 2016
(This article belongs to the Special Issue Computational Design: A New Approach to Drug and Molecular Discovery)
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Abstract

Expanded (x) and widened (y) deoxyribose nucleic acids (DNA) have an extra benzene ring incorporated either horizontally (xDNA) or vertically (yDNA) between a natural pyrimidine base and the deoxyribose, or between the 5- and 6-membered rings of a natural purine. Far-reaching applications for (x,y)DNA include nucleic acid probes and extending the natural genetic code. Since modified nucleobases must encode information that can be passed to the next generation in order to be a useful extension of the genetic code, the ability of translesion (bypass) polymerases to replicate modified bases is an active area of research. The common model bypass polymerase DNA polymerase IV (Dpo4) has been previously shown to successfully replicate and extend past a single modified nucleobase on a template DNA strand. In the current study, molecular dynamics (MD) simulations are used to evaluate the accommodation of expanded/widened nucleobases in the Dpo4 active site, providing the first structural information on the replication of (x,y)DNA. Our results indicate that the Dpo4 catalytic (palm) domain is not significantly impacted by the (x,y)DNA bases. Instead, the template strand is displaced to accommodate the increased C1’–C1’ base-pair distance. The structural insights unveiled in the present work not only increase our fundamental understanding of Dpo4 replication, but also reveal the process by which Dpo4 replicates (x,y)DNA, and thereby will contribute to the optimization of high fidelity and efficient polymerases for the replication of modified nucleobases. View Full-Text
Keywords: expanded DNA; xDNA; widened DNA; yDNA; DNA replication; translesion synthesis; bypass polymerase; Dpo4; molecular dynamics expanded DNA; xDNA; widened DNA; yDNA; DNA replication; translesion synthesis; bypass polymerase; Dpo4; molecular dynamics
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Albrecht, L.; Wilson, K.A.; Wetmore, S.D. Computational Evaluation of Nucleotide Insertion Opposite Expanded and Widened DNA by the Translesion Synthesis Polymerase Dpo4. Molecules 2016, 21, 822.

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