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DNA Polymerase lambda Active Site Favors a Mutagenic Mispair between the Enol Form of Deoxyguanosine Triphosphate Substrate and the Keto Form of Thymidine Template: A Free Energy Perturbation Study
Loyola Univ, Dept Chem & Biochem, 1032 W Sheridan Rd, Chicago, IL 60660 USA..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.ORCID iD: 0000-0002-3190-1173
Loyola Univ, Dept Chem & Biochem, 1032 W Sheridan Rd, Chicago, IL 60660 USA..
2017 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 121, no 33, 7813-7822 p.Article in journal (Refereed) Published
Abstract [en]

Human DNA polymerise lambda is an intermediate fidelity member of the X family, which plays a role in DNA repair. Recent X-ray diffraction structures of a ternary complex of a loop-deletion mutant of polymerase 2, a deoxyguanosine triphosphate analogue, and a gapped DNA show that guanine and thymine form a mutagenic mispair with an . unexpected Watson Crick-like geometry rather than a wobble geometry. Hence, there is an intriguing possibility that either thyMine in the DNA or guanine in the deoxyguanosine triphosphate analogue may Spend, a substantial fraction of time in a deprotonated or enol form (both are minor species in aqueous solution) in the active site of the,polymerase lambda mutant. The experiments do not determine particular forms of the nucleobases that contribute to this mutagenic mispair. Thus, We investigate the thermodynamics of formation of various mispairs between guanine and thymine in the ternary complex at a neutral pH using classical molecular dynamics simulations and the free energy perturbation method. Our free energy calculations, as well as a comparison of the experimental and computed structures of mispairs, indicate that the Watson-Crick-like mispair between the enol tautomer of guanine and the keto tautomer of thymine is dominant. The wobble mispair between the keto forms of guanine and thymine and the Watson Crick-like mispair between the keto tautomer of guanine and the enol tautomer of thymine are less prevalent, and mispairs that involve deprotonated guanine or thymine are thermodynamically unlikely. These findings are consistent with the experiment and relevant for understanding mechanisms of spontaneous mutagenesis.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017. Vol. 121, no 33, 7813-7822 p.
National Category
Structural Biology Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-335232DOI: 10.1021/acs.jpcb.7b04874ISI: 000408598300009PubMedID: 28732447OAI: oai:DiVA.org:uu-335232DiVA: diva2:1162908
Available from: 2017-12-05 Created: 2017-12-05 Last updated: 2017-12-05Bibliographically approved

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Kamerlin, Shina Caroline Lynn

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