Publication details
Cisplatin GG-crosslinks within single-stranded DNA: Origin of the preference for left-handed helicity
| Authors | |
|---|---|
| Year of publication | 2012 |
| Type | Article in Periodical |
| Magazine / Source | Journal of Inorganic Biochemistry |
| MU Faculty or unit | |
| Citation | |
| Doi | http://dx.doi.org/10.1016/j.jinorgbio.2012.05.015 |
| Field | Macromolecular chemistry |
| Keywords | Anticancer drugs; Cisplatin; DNA binding; Intrastrand crosslinks; Molecular dynamics simulations; NMR spectroscopy |
| Description | Molecular dynamics (MD) simulations of the single-stranded DNA trinucleotide TG*G*, with the G* guanines crosslinked by the antitumor drug cisplatin, were performed with explicit representation of the water as solvent. The purpose of the simulations was to explain previous NMR observations indicating that in singlestranded cisplatin-DNA adducts, the crosslinked guanines adopt a left-handed helical orientation, whereas in duplexes, the orientation is right handed. The analysis of the MD trajectory of TG*G* has ascribed a crucial role to hydrogen-bonding (direct or through water) interactions of the 5prime oriented NH3 ligand of platinum with acceptor groups at the 5prime-side of the crosslink, namely the TpG* phosphate and the terminal 5prime OH group. These interactions bring about some strain into the trinucleotide which is slightly but significantly (1 to 1.5 kcal/mol) higher for the right-handed orientation than for the left-handed one. During the unconstrained, 3 ns long MD simulation, left handed conformations were ~15 times more abundant than the right handed ones. This sampling difference agrees roughlywith the calculated energy difference in strain energy. Overall, these results show that the Pt GG crosslink within single stranded DNA ismalleable and can access different conformations at a moderate energy cost. This malleability could be of importance in interactions between the platinated DNA and cellular proteins, in which the DNA is locally unwound. |