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

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