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A QM/MM Investigation of Thymine Dimer Radical Anion Splitting Catalyzed by DNA Photolyase


Masson, F; Laino, T; Rothlisberger, U; Hutter, J (2008). A QM/MM Investigation of Thymine Dimer Radical Anion Splitting Catalyzed by DNA Photolyase. ChemPhysChem, 10(2):400-410.

Abstract

DNA photolyase is a highly efficient light-driven enzyme that repairs the UV-induced cyclobutane pyrimidine dimer in damaged DNA. Herein, we investigate the repair reaction of the thymine dimer by means of hybrid quantum mechanical/molecular mechanical QM/MM) dynamics simulations based on the X-ray structure of on enzyme-DNA complex. In analogy to the self-repair reaction, we find that the splitting mechanism of the cyclobutane ring is asynchronously concerted and is complete within a few picoseconds upon electron uptake. A few distinct processes characterize the dynamics of splitting of the thymine dimer radical anion within the DNA photolyase active site: continuous solvation reordering of the catalytic region, proton transfer from Glu283 to the dimer, as well as tight interactions of the cationic side chains of Arg232 and Arg350 with the thymine dimer. This points to the important role of the active-site hydrogen bond and salt-bridge patterns in stabilizing the thymine dimer anion and slowing down the electron back-transfer process. Comparison of the repair efficiency with respect to the self-repair reaction is also discussed.

DNA photolyase is a highly efficient light-driven enzyme that repairs the UV-induced cyclobutane pyrimidine dimer in damaged DNA. Herein, we investigate the repair reaction of the thymine dimer by means of hybrid quantum mechanical/molecular mechanical QM/MM) dynamics simulations based on the X-ray structure of on enzyme-DNA complex. In analogy to the self-repair reaction, we find that the splitting mechanism of the cyclobutane ring is asynchronously concerted and is complete within a few picoseconds upon electron uptake. A few distinct processes characterize the dynamics of splitting of the thymine dimer radical anion within the DNA photolyase active site: continuous solvation reordering of the catalytic region, proton transfer from Glu283 to the dimer, as well as tight interactions of the cationic side chains of Arg232 and Arg350 with the thymine dimer. This points to the important role of the active-site hydrogen bond and salt-bridge patterns in stabilizing the thymine dimer anion and slowing down the electron back-transfer process. Comparison of the repair efficiency with respect to the self-repair reaction is also discussed.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Date:17 December 2008
Deposited On:31 Jul 2009 09:00
Last Modified:05 Apr 2016 13:13
Publisher:Wiley-Blackwell
ISSN:1439-4235
Additional Information:Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Publisher DOI:10.1002/cphc.200800624
Official URL:http://www3.interscience.wiley.com/cgi-bin/fulltext/121575183/PDFSTART
Permanent URL: http://doi.org/10.5167/uzh-18393

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