A STRUCTURAL BASIS FOR A PHOSPHORAMIDE MUSTARD-INDUCED DNA INTERSTRAND CROSS-LINK AT 5'-D(GAC)

Phosphoramide mustard-induced DNA interstrand cross-links were studied both in vitro and by computer simulation, The local determinants for the formation of phosphoramide mustard-induced DNA interstrand crossli nks were defined by using different pairs of synthetic oligonucleotide duplexes, each of which contained a single potentially cross-linkable site. Phosphoramide mustard was found to cross-link dG to dG at a 5'- d(GAC)-3', The structural basis for the formation of this 1,3 cross-li nk was studied by molecular dynamics and quantum chemistry, Molecular dynamics indicated that the geometrical proximity of the binding sites also favored a 1,3 dG-to-dG linkage over a 1,2 dG-to-dG linkage in a 5'-d(GCC)-3' sequence, While the enthalpies of 1,2 and 1,3 mustard cro ss-linked DNA were found to be very close, a 1,3 structure was more fl exible and may therefore be in a considerably higher entropic state.