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Department of Chemistry and Courant Institute of Mathematical Sciences, New York University, New York, New York 10012-2005, USA
(RECEIVED July 25, 2005; FINAL REVISION October 10, 2005; ACCEPTED October 11, 2005)
The possible conformational changes of DNA polymerase IV (Dpo4) before and after the nucleotidyl-transfer reaction are investigated at the atomic level by dynamics simulations to gain insight into the mechanism of low-fidelity polymerases and identify slow and possibly critical steps. The absence of significant conformational changes in Dpo4 before chemistry when the incoming nucleotide is removed supports the notion that the "induced-fit" mechanism employed to interpret fidelity in some replicative and repair DNA polymerases does not exist in Dpo4. However, significant correlated movements in the little finger and finger domains, as well as DNA sliding and subtle catalytic-residue rearrangements, occur after the chemical reaction when both active-site metal ions are released. Subsequently, Dpo4’s little finger grips the DNA through two arginine residues and pushes it forward. These metal ion correlated movements may define subtle, and possibly characteristic, conformational adjustments that operate in some Y-family polymerase members in lieu of the prominent subdomain motions required for catalytic cycling in other DNA polymerases like polymerase 
. Such subtle changes do not easily provide a tight fit for correct incoming substrates as in higher-fidelity polymerases, but introduce in low-fidelity polymerases different fidelity checks as well as the variable conformational-mobility potential required to bypass different lesions.
Keywords: Dpo4; dynamics simulations; replication mechanism; conformational changes; catalytic metal ion; nucleotide-binding metal ion
Abbreviations: Dpo4, Sulfolobus solfataricus P2 DNA polymerase IV • 8-oxoG, 8-oxoguanine • pol , DNA polymerase • RMSD, root-mean- square deviation • dCTP, 2'-deoxyribocytidine 5'-triphosphate • dNTP, 2'-deoxyribonucleoside 5'-triphosphate • ddATP, 2',3'-dideoxyriboadenosine 5'-triphosphate • LF, little finger • PPi, pyrophosphate • PCA, principal component analysis • bp, base pair
Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051726906.
Reprint requests to: Tamar Schlick, Department of Chemistry and Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, NY 10012-2005, USA; e-mail: schlick{at}nyu.edu; fax: (212) 995-4152.
Supplemental material: see www.proteinscience.org
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