title: A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC).
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.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Dong
authors.forename: D
authors.initials: D
authors.lastname: Barsky
authors.forename: M E
authors.initials: ME
authors.lastname: Colvin
authors.forename: C F
authors.initials: CF
authors.lastname: Melius
authors.forename: S M
authors.initials: SM
authors.lastname: Ludeman
authors.forename: J F
authors.initials: JF
authors.lastname: Moravek
authors.forename: O M
authors.initials: OM
authors.lastname: Colvin
authors.forename: D D
authors.initials: DD
authors.lastname: Bigner
authors.forename: P
authors.initials: P
authors.lastname: Modrich
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D001483:Base Sequence; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D006868:Hydrolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D010752:Phosphoramide Mustards / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D003432:Cross-Linking Reagents; D009838:Oligodeoxyribonucleotides; D010752:Phosphoramide Mustards; C030090:phosphoramide mustard; D004247:DNA