Q. Dong et al., A STRUCTURAL BASIS FOR A PHOSPHORAMIDE MUSTARD-INDUCED DNA INTERSTRAND CROSS-LINK AT 5'-D(GAC), Proceedings of the National Academy of Sciences of the United Statesof America, 92(26), 1995, pp. 12170-12174
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.