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Cisplatin Adducts on a GGG Sequence within a DNA Duplex Studied by NMR Spectroscopy and Molecular Dynamics Simulations
Author(s) -
Téletchéa Stéphane,
Skauge Tormod,
Sletten Einar,
Kozelka Jiří
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200901158
Subject(s) - adduct , crystallography , chemistry , nuclear magnetic resonance spectroscopy , stereochemistry , molecular dynamics , duplex (building) , dna , computational chemistry , organic chemistry , biochemistry
The antitumor drug cisplatin ( cis ‐[PtCl 2 (NH 3 ) 2 ]) reacts with cellular DNA to form GG intrastrand adducts between adjacent guanines as predominant lesions. GGG sites have been shown to be hotspots of platination. To study the structural perturbation induced by binding of cisplatin to two adjacent guanines of a GGG trinucleotide, we examined here the decanucleotide duplex d[(G 1 C 2 C 3 ${{\rm G}{{{\ast}\hfill \atop 4\hfill}}}$ ${{\rm G}{{{\ast}\hfill \atop 5\hfill}}}$ G 6 T 7 ‐ C 8 G 9 C 10 ) ⋅ d(G 11 C 12 G 13 A 14 C 15 C 16 C 17 G 18 ‐ G 19 C 20 )] ( dsCG*G*G ) intrastrand cross‐linked at the G* guanines by cis ‐{Pt(NH 3 ) 2 } 2+ using NMR spectroscopy and molecular dynamics (MD) simulations. The NMR spectra of dsCG*G*G were found to be similar to those of previously characterized DNA duplexes cross‐linked by cisplatin at a pyG*G*X site (py=pyrimidine; X=C, T, A). This similarity of NMR spectra indicates that the base at the 3′‐side of the G*G*–Pt cross‐link does not affect the structure to a large extent. An unprecedented reversible isomerization between the duplex dsCG*G*G (bearing a ${{\rm G}{{{\ast}\hfill \atop 4\hfill}}}$ ${{\rm G}{{{\ast}\hfill \atop 5\hfill}}}$ –Pt chelate) and duplex dsGG*G*T (bearing a ${{\rm G}{{{\ast}\hfill \atop 5\hfill}}}$ ${{\rm G}{{{\ast}\hfill \atop 6\hfill}}}$ –Pt chelate) was observed, which yielded a 40:60 equilibrium between the two intrastrand GG–Pt cross‐links. No formation of interstrand cross‐links was observed. NMR spectroscopic data of dsCG*G*G indicated that the deoxyribose of the 5′‐G* adopts an N‐type conformation, and the cytidines C 3 , C 15 , and C 16 have average phase angles intermediate between S and N. The NMR spectroscopic chemical shifts of dsGG*G*T showed some fundamental differences to those of pyG*G*–platinum adducts but were in agreement with the NMR spectra reported previously for the DNA duplexes cross‐linked at an AG*G*C sequence by cisplatin or oxaliplatin. The presence of a purine instead of a pyrimidine at the 5′‐side of the G*G* cross‐link seems therefore to affect the structure of the XG* step significantly.