Structural damage in certain specific oncogenes and tumor suppressor genes may trigger initiation of multi-stage chemical carcinogenesis. Aromatic amines are among the most notorious environmental carcinogens. Nucleotide excision repair (NER) is the major cellular pathway for removing such bulky DNA lesions. DNA damage recognition in NER is governed by adducts structures and their influences on base pairings at the lesion site as well as the nature of neighboring and distant base sequences. Molecular Dynamics (MD)-based Potential of Mean Force (PMF) calculations were employed to study base flipping at such lesion sites to investigate the sequence and lesion effects.  Conformations sampled correspond with those observed in NMR experiments for both NOE distance restraints and global structures. Free energy profiles along the base flipping reaction coordinate for the lesions are in agreement with 19F NMR experimental data. The results provided insights into mechanisms of sequence dependent NER.

Potential of mean force calculations on base flipping of carcinogen-modified base in DNA duplexes

244th National Meeting (2012)

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