ONIOM Study on the DNA Interstrand Crosslinks by the Chloroethylnitrosoureas

Chloroethylnitrosoureas (CENUs) are clinically useful anticancer agents. Their cytotoxicity has been proved to be associated with the generation of DNA interstrand crosslinks. In the present work, QM/MM computations are carried out to investigate the crosslinks of DNA complementary bases by the CENUs with ONIOM hybrid method. DNA double helix containing crosslinked base pairs are established as the computational models. The crosslinked DNA are subdivided into three layers, each of which are described at B3LYP/6-311+G(d,p), AM1 and UFF level of theory respectively. The result shows that the covalent crosslink between guanine N¹ and complementary cytosine N³ is the most favorable crosslinking product. This crosslink is characterized by its less deformation of DNA double helix and higher stability than the other crosslinks on the complementary base pairs. The results of the ONIOM computations explain the phenomenon that 1-(N³-deoxycytidyl)-2-(N¹-deoxyguanosinyl)ethane is the main crosslink product in the in vivo an the in vitro experiments.