Processive Incorporation of Deoxynucleoside Triphosphate Analogs by Single-Molecule DNA Polymerase I (Klenow Fragment) Nanocircuits. 2015

Kaitlin M Pugliese, and O Tolga Gul, and Yongki Choi, and Tivoli J Olsen, and Patrick C Sims, and Philip G Collins, and Gregory A Weiss
Departments of †Chemistry, §Physics and Astronomy, and ⊥Molecular Biology and Biochemistry, University of California, Irvine, California 92697, United States.

DNA polymerases exhibit a surprising tolerance for analogs of deoxyribonucleoside triphosphates (dNTPs), despite the enzymes' highly evolved mechanisms for the specific recognition and discrimination of native dNTPs. Here, individual DNA polymerase I Klenow fragment (KF) molecules were tethered to a single-walled carbon nanotube field-effect transistor (SWCNT-FET) to investigate accommodation of dNTP analogs with single-molecule resolution. Each base incorporation accompanied a change in current with its duration defined by τclosed. Under Vmax conditions, the average time of τclosed was similar for all analog and native dNTPs (0.2 to 0.4 ms), indicating no kinetic impact on this step due to analog structure. Accordingly, the average rates of dNTP analog incorporation were largely determined by durations with no change in current defined by τopen, which includes molecular recognition of the incoming dNTP. All α-thio-dNTPs were incorporated more slowly, at 40 to 65% of the rate for the corresponding native dNTPs. During polymerization with 6-Cl-2APTP, 2-thio-dTTP, or 2-thio-dCTP, the nanocircuit uncovered an alternative conformation represented by positive current excursions that does not occur with native dNTPs. A model consistent with these results invokes rotations by the enzyme's O-helix; this motion can test the stability of nascent base pairs using nonhydrophilic interactions and is allosterically coupled to charged residues near the site of SWCNT attachment. This model with two opposing O-helix motions differs from the previous report in which all current excursions were solely attributed to global enzyme closure and covalent-bond formation. The results suggest the enzyme applies a dynamic stability-checking mechanism for each nascent base pair.

UI MeSH Term Description Entries
D011122 Polyphosphates Linear polymers in which orthophosphate residues are linked with energy-rich phosphoanhydride bonds. They are found in plants, animals, and microorganisms. Polyphosphate
D003854 Deoxyribonucleotides A purine or pyrimidine base bonded to a DEOXYRIBOSE containing a bond to a phosphate group. Deoxyribonucleotide
D004256 DNA Polymerase I A DNA-dependent DNA polymerase characterized in prokaryotes and may be present in higher organisms. It has both 3'-5' and 5'-3' exonuclease activity, but cannot use native double-stranded DNA as template-primer. It is not inhibited by sulfhydryl reagents and is active in both DNA synthesis and repair. DNA Polymerase alpha,DNA-Dependent DNA Polymerase I,Klenow Fragment,DNA Pol I,DNA Dependent DNA Polymerase I,Polymerase alpha, DNA
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D037742 Nanotubes, Carbon Nanometer-sized tubes composed mainly of CARBON. Such nanotubes are used as probes for high-resolution structural and chemical imaging of biomolecules with ATOMIC FORCE MICROSCOPY. Buckytubes,Carbon Nanotubes,Nanoribbons,Buckytube,Carbon Nanotube,Nanoribbon,Nanotube, Carbon

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