COMPUTATIONAL SIMULATIONS OF DNA DISTORTIONS BY A CIS,SYN-CYCLOBUTANETHYMINE DIMER LESION

Results are presented from 500 ps molecular dynamics simulations on th e native dodecamer d(CGCGAATTCGCG)(2) and the lesioned dodecamer conta ining a cis,syn-thymine cyclobutane dimer at the TT step. The computat ions, performed with AMBER4.1, included explicitly represented solvent with periodic boundary conditions applied within the constant tempera ture and pressure algorithm. Electrostatic interactions were calculate d with the particle-mesh Ewald method. Distortions to DNA structure pr oduced by the lesion were found to be localized at the dimer site and include mainly a substantial kink in the helical axis, rolled and tilt ed base pairs, and weakened hydrogen bonding at the 5' base pair of th e lesion. A slight change in orientation around the glycosyl bond for the 5' thymine of the lesion and highly stiffened deoxyribose rings fo r both thymine bases were also observed. The global curvature of DNA i s increased by about 10 degrees by dimer Incorporation. Calculations o f H(1')-H(6)(pyrimidine) and H(1')-H(8)-(purine) interproton distances from the performed simulations agree very well with the pattern of NM R NOE signals reported in various dimer containing oligonucleotides, w here an interruption of NOE connectivities is found on the 5' side of the lesion. Comparison of the pattern of distortions observed at the d imer site with the crystal structure of a complex between dimer-contai ning DNA and repair enzyme endonuclease V (Cell 1995, 83, 773-782) lea ds to the hypothesis that dimer recognition may involve a whole patter n of small distortion at the lesion site rather than one particular st ructural/dynamical feature associated with the lesion.