Combined Quantum and Molecular Mechanical Study of DNA Cross-Linking by Nitrous Acid

摘要

Interstrand cross-linking of DNA is believed to be responsible for the biological activity of a number of antitumor agents, many of which exhibit some degree of sequence selectivity in their interactions with DNA. Despite the experimental interest in cross-linking reactions, their theoretical study has up to now received only limited attention. Molecular mechanics (MM) calculations, for example, have been used to provide some insight into the likely structural effects of cross-linking, but studies of the reaction processes themselves have been prevented by the need for a quantum mechanical (QM) treatment. Recently developed combined QM-MM potential functions allow reactions in large systems to be studied by considering a small QM region influenced by a surrounding MM region. Here such an approach is applied to reactions in DNA and is used to investigate the sequence preferences of DNA cross-linking by nitrous acid.