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Title: Computational simulations of DNA distortions by a cis,syn-cyclobutane thymine dimer lesion

Abstract

Results are presented from 500 ps molecular dynamics simulations on the native dodecamer d(CGC-GAATTCGCG){sub 2} and the lesioned dodecamer containing a cis,syn-thymine cyclobutane dimer at the TT step. The computations, performed with AMBER4.l, included explicitly represented solvent with periodic boundary conditions applied within the constant temperature and pressure algorithm. Electrostatic interactions were calculated with the particle-mesh Ewald method. Distortions to DNA structure produced by the lesion were found to be localized at the dimer site and include mainly a substantial kink in the helical axis, rolled and tilted base pairs, and weakened hydrogen bonding at the 5` base pair of the lesion. A slight change in orientation around the glycosyl bond for the 5` thymine of the lesion and highly stiffened deoxyribose rings for both thymine bases were also observed. The global curvature of DNA is increased by about 10{degree} by dimer incorporation. Calculations of H(1`)-H(6)(pyrimidine) and H(1`)-H(8)-(purine) interproton distances from the performed simulations agree very well with the pattern of NMR NOE signals reported in various dimer containing oligonucleotides, where an interruption of NOE connectivities is found on the 5` side of the lesion. 40 refs., 8 figs., 1 tab.

Authors:
; ;  [1];  [2]
  1. Pacific Northwest National Lab., Richland, WA (United States)
  2. Mount Sinai School of Medicine, New York, NY (United States)
Publication Date:
OSTI Identifier:
420823
DOE Contract Number:
AC06-76RL01830; FG02-88ER60675
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of the American Chemical Society; Journal Volume: 118; Journal Issue: 38; Other Information: PBD: 25 Sep 1996
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; 40 CHEMISTRY; 99 MATHEMATICS, COMPUTERS, INFORMATION SCIENCE, MANAGEMENT, LAW, MISCELLANEOUS; SKIN; RADIATION EFFECTS; DNA; MOLECULAR MODELS; ORGANIC COMPOUNDS; CALCULATION METHODS; COMPUTER CODES; COMPUTERIZED SIMULATION; NEOPLASMS; BIOCHEMISTRY

Citation Formats

Miaskiewicz, K., Miller, J., Cooney, M., and Osman, R.. Computational simulations of DNA distortions by a cis,syn-cyclobutane thymine dimer lesion. United States: N. p., 1996. Web. doi:10.1021/ja9611304.
Miaskiewicz, K., Miller, J., Cooney, M., & Osman, R.. Computational simulations of DNA distortions by a cis,syn-cyclobutane thymine dimer lesion. United States. doi:10.1021/ja9611304.
Miaskiewicz, K., Miller, J., Cooney, M., and Osman, R.. 1996. "Computational simulations of DNA distortions by a cis,syn-cyclobutane thymine dimer lesion". United States. doi:10.1021/ja9611304.
@article{osti_420823,
title = {Computational simulations of DNA distortions by a cis,syn-cyclobutane thymine dimer lesion},
author = {Miaskiewicz, K. and Miller, J. and Cooney, M. and Osman, R.},
abstractNote = {Results are presented from 500 ps molecular dynamics simulations on the native dodecamer d(CGC-GAATTCGCG){sub 2} and the lesioned dodecamer containing a cis,syn-thymine cyclobutane dimer at the TT step. The computations, performed with AMBER4.l, included explicitly represented solvent with periodic boundary conditions applied within the constant temperature and pressure algorithm. Electrostatic interactions were calculated with the particle-mesh Ewald method. Distortions to DNA structure produced by the lesion were found to be localized at the dimer site and include mainly a substantial kink in the helical axis, rolled and tilted base pairs, and weakened hydrogen bonding at the 5` base pair of the lesion. A slight change in orientation around the glycosyl bond for the 5` thymine of the lesion and highly stiffened deoxyribose rings for both thymine bases were also observed. The global curvature of DNA is increased by about 10{degree} by dimer incorporation. Calculations of H(1`)-H(6)(pyrimidine) and H(1`)-H(8)-(purine) interproton distances from the performed simulations agree very well with the pattern of NMR NOE signals reported in various dimer containing oligonucleotides, where an interruption of NOE connectivities is found on the 5` side of the lesion. 40 refs., 8 figs., 1 tab.},
doi = {10.1021/ja9611304},
journal = {Journal of the American Chemical Society},
number = 38,
volume = 118,
place = {United States},
year = 1996,
month = 9
}
  • Cited by 17
  • Molecular dynamics simulations were preformed on the DNA dodecamers CGCGAATTCGCG and GCACGAATTAAG, where TT denotes a thymine dimer. The constant temperature and pressure algorithm of AMBER 4.1 was used with explicit water and counterions, periodic boundary conditions, and electrostatic interactions evaluated by the particle-mesh Ewald method. Results were analyzed by the CURVES algorithm and its implementation in DIALS and WINDOWS. Calculated distortions of DNA structure were qualitatively and quantitatively similar for the two sequences. Despite the enhanced flexibility of the native TpA dinucleotide step, major deviations from the B-DNA values of helicoidal parameters were found only at the ApT andmore » TpT dinucleotide steps in both sequences. Hence, we conclude that the pattern of structural perturbations responsible for recognition of thymine dimers by repair enzymes is not sensitive to their sequence context.« less
  • We have constructed a single-stranded vector that contains a uniquely located cis-syn T-T cyclobutane dimer by ligating a synthetic oligomer containing this UV photoproduct into M13mp7 viral DNA linearized with EcoRI. In the absence of SOS induction, transfection of a uvrA6 mutant of Escherichia coli with this vector gave very few progeny plaques, and the data imply that a single dimer blocks replication in at least 99.5% of the molecules. In vitro photoreactivation completely abolished this inhibition. Transfection of cells irradiated with UV at 4 J.m-2 to induce the SOS response gave 27% of the number of plaques found withmore » a dimer-free control. Nucleotide sequence analysis of 529 progeny phage showed that translesion synthesis was usually accurate: the normal sequence was found in 93% of them. Where mutations occurred, all were targeted single-nucleotide substitutions, with approximately 90% being targeted at the 3' nucleotide of the lesion: of a total of 26 mutations, 15 were 3' T----A, 8 were 3' T----C, and 3 were 5' T----C. No T----G mutations were found. In addition to these results with the normal construct, data were also obtained from vectors in which the M13mp7 cloning site, which forms a hairpin in single-stranded DNA, was present 4 nucleotides on the 3' side of the T-T dimer. These hairpin-containing vectors gave a very similar mutation frequency (8% versus 7%) but altered mutation spectrum: all 12 mutations detected were 3' T----A transversions, a difference from the previous set of data that is significant (P = 0.03).« less
  • The solution structures of a duplex DNA dodecamer containing a cis-syn cyclobutane thymine dimer d(GCACGAAT[cs]TAAG).d(CTTAATTCG TGC) and its native parent sequence were determined using NMR data collected at 750 MHz. The dodecamer sequence corresponds to the section of a site-specific cis-syn dimer containing 49-mer that was found to be the binding site for the dimer-specific T4 denV endonuclease V repair enzyme by chemical and enzymatic footprinting experiments. Structures of both sequences were derived from NOE restrained molecular dynamics/simulated annealing calculations using a fixed outer layer of water and an inner dynamic layer of water with sodium counterions. The resulting structuresmore » reveal a subtle distortion to the phosphodiester backbone in the dimer-containing sequence which includes a BII phosphate at the T9pA10 junction immediately 3' to the dimer. The BII phosphate, established experimentally by analysis of the 31P chemical shifts and interpretation of the 3JP-H3' values using an optimized Karplus relationship, enables the DNA helix to accommodate the dimer by destacking the base 3' to the dimer. Furthermore, the structures provide explanations for the unusually shifted T8-N3H imino, A16-H2 and T8-Me proton resonances and T9pA10 (31)P NMR resonance and are consistent with bending, unwinding, and thermodynamic data.« less