Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse

Proceedings of the National Academy of Sciences of the United States of America
Lalith PereraSamuel H Wilson

Abstract

DNA polymerases facilitate faithful insertion of nucleotides, a central reaction occurring during DNA replication and repair. DNA synthesis (forward reaction) is "balanced," as dictated by the chemical equilibrium by the reverse reaction of pyrophosphorolysis. Two closely spaced divalent metal ions (catalytic and nucleotide-binding metals) provide the scaffold for these reactions. The catalytic metal lowers the pKa of O3' of the growing primer terminus, and the nucleotide-binding metal facilitates substrate binding. Recent time-lapse crystallographic studies of DNA polymerases have identified an additional metal ion (product metal) associated with pyrophosphate formation, leading to the suggestion of its possible involvement in the reverse reaction. Here, we establish a rationale for a role of the product metal using quantum mechanical/molecular mechanical calculations of the reverse reaction in the confines of the DNA polymerase β active site. Additionally, site-directed mutagenesis identifies essential residues and metal-binding sites necessary for pyrophosphorolysis. The results indicate that the catalytic metal site must be occupied by a magnesium ion for pyrophosphorolysis to occur. Critically, the product metal site is oc...Continue Reading

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Citations

Aug 18, 2016·Journal of the American Chemical Society·Vito GennaMarco De Vivo
Jan 22, 2017·Nucleic Acids Research·Lalith PereraSamuel H Wilson
Apr 19, 2018·Metallomics : Integrated Biometal Science·Stefan K KolevGeorgi N Vayssilov
Jan 18, 2018·Proceedings of the National Academy of Sciences of the United States of America·Cassandra R Burke, Andrej Lupták
Oct 29, 2018·Protein Science : a Publication of the Protein Society·Jimin Wang, Zachary B Smithline
Oct 29, 2018·Protein Science : a Publication of the Protein Society·Ming-Daw Tsai
Aug 2, 2017·Nature Chemical Biology·David D ShockSamuel H Wilson
Aug 16, 2017·Nature Communications·Joonas A JamsenSamuel H Wilson
Sep 25, 2020·Chemistry : a European Journal·Jigang LvDayong Yang
Nov 24, 2019·Proceedings of the National Academy of Sciences of the United States of America·Daniel RostonQiang Cui
Jul 29, 2017·Scientific Reports·Igor P SmirnovEdward N Timofeev
Mar 15, 2018·Chemical Communications : Chem Comm·Marc A van BochoveF Matthias Bickelhaupt
Jul 9, 2020·ACS Omega·Lalith PereraSamuel H Wilson
Apr 8, 2021·Nature Communications·Joonas A JamsenSamuel H Wilson
Feb 10, 2018·Journal of the American Chemical Society·Vito GennaMarco De Vivo
Jan 23, 2018·Journal of Chemical Information and Modeling·Swati R Manjari, Nilesh K Banavali
Jun 23, 2018·Journal of the American Chemical Society·David R Stevens, Sharon Hammes-Schiffer
Aug 22, 2021·Nature Communications·Joonas A JamsenSamuel H Wilson

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