MOLECULAR-DYNAMICS SIMULATIONS OF THE EFFECTS OF RING-SATURATED THYMINE LESIONS ON DNA-STRUCTURE

The effect of thymine lesions produced by radiation or oxidative damag e on DNA structure was studied by molecular dynamics simulations of na tive and damaged DNA. Thymine in position 7 of native dodecamer d(CGCG AATTCGCG)(2) was replaced by one of the four thymine lesions 5-hydroxy -5,6-dihydrothymine, 6-hydroxy-5,6-dihydrothymine (thymine photohydrat e), 5,6-dihydroxy-5,6-dihydro-thymine (thymine glycol), and 5,6-dihydr othymine. Simulations were performed with Assisted Model Building with Energy Refinement force field. Solvent was represented by a rectangul ar box of water with periodic boundary conditions applied. A constant temperature and constant volume protocol was used The observed level o f distortions of DNA structure depends on the specific nature of the l esion. The 5,6-dihydrothymine does not cause distinguishable perturbat ions to DNA. Other lesions produce a dramatic increase in the rise par ameter. between the lesion and the 5' adjacent adenine. These changes are accompanied by weakening of Watson-Crick hydrogen bonds in the A6- T19 base pair on the 5' side of the lesion. The lesioned bases also sh ow negative values of inclination relative to the helical axis. No cha nges in the pattern of backbone torsional angles are observed with any of the lesions incorporated into DNA. The structural distortions in D NA correlate well with known biological effects of 5,6-dihydrothymine and thymine glycol on such processes as polymerase action or recogniti on by repair enzymes. (C) 1995 John Wiley & Sons, Inc.