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. 1995 Dec 19;92(26):12170–12174. doi: 10.1073/pnas.92.26.12170

A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC).

Q Dong 1, D Barsky 1, M E Colvin 1, C F Melius 1, S M Ludeman 1, J F Moravek 1, O M Colvin 1, D D Bigner 1, P Modrich 1, H S Friedman 1
PMCID: PMC40318  PMID: 8618865

Abstract

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 cross-links 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-link 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 cross-linked DNA were found to be very close, a 1,3 structure was more flexible and may therefore be in a considerably higher entropic state.

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