Molecular dynamics simulations of the effects of ring‐saturated thymine lesions on DNA structure

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Abstract
The effect of thymine lesions produced by radiation or oxidative damage on DNA structure was studied by molecular dynamics simulations of native and damaged DNA. Thymine in position 7 of native dodecamer d(CGCGAATTCGCG)2 was replaced by one of the four thymine lesions 5‐hydroxy‐5,6‐dihydrothymine, 6‐hydroxy‐5,6‐dihydrothymine (thymine photohydrate), 5,6‐dihydmxy‐5,6‐dihydro‐thymine (thymine glycol), and 5,6‐dihydmthymine. Simulations were performed with Assisted Model Building with Energy Refinement force field. Solvent was represented by a rectangular box of water with periodic boundary conditions applied. A constant temperature and constant volume protocol was used, the observed level of distortions of DNA structure depends on the specific nature of the lesion. The 5,6‐dihydrothymine does not cause distinguishable perturbations to DNA. Other lesions produce a dramatic increase in the rise parameter 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 show negative values of inclination relative to the helical axis. No changes in the pattern of backbone torsional angles are observed with any of the lesions incorporated into DNA. The structural distortions in DNA correlate well with known biological effects of 5,6‐dihydrothymine and thymine glycol on such processes as polymerase action or recognition by repair enzymes. © 1995 John Wiley & Sons, Inc.