resumo
We report DNA binding studies of the dinuclear ruthenium ligand [{Ru(phen)(2)}(2)tpphz](4+) in enantiomerically pure forms. As expected from previous studies of related complexes, both isomers bind with similar affinity to B-DNA and have enhanced luminescence. However, when tested against the G-quadruplex from human telomeres (which we show to form an antiparallel basket structure with a diagonal loop across one end), the Lambda Lambda isomer binds approximately 40 times more tightly than the Delta Delta, with a stronger luminescence. NMR studies show that the complex binds at both ends of the quadruplex. Modeling studies, based on experimentally derived restraints obtained for the closely related [{Ru(bipy)(2)}(2)tpphz](4+), show that the Lambda Lambda isomer fits neatly under the diagonal loop, whereas the Delta Delta isomer is unable to bind here and binds at the lateral loop end. Molecular dynamics simulations show that the Delta Delta isomer is prevented from binding under the diagonal loop by the rigidity of the loop. We thus present a novel enantioselective binding substrate for antiparallel basket G-quadruplexes, with features that make it a useful tool for quadruplex studies.
palavras-chave
G-QUADRUPLEX DNA; INTRAMOLECULAR G-QUADRUPLEX; PARTICLE MESH EWALD; AMBER FORCE-FIELD; K+ SOLUTION; CRYSTAL-STRUCTURE; METAL-COMPLEXES; MOLECULAR-DYNAMICS; DRUG RECOGNITION; PROMOTER REGION
categoria
Pharmacology & Pharmacy
autores
Wilson, T; Costa, PJ; Felix, V; Williamson, MP; Thomas, JA
nossos autores
Paulo Jorge Ferreira de Matos Costa
Bolseiro de pós-Doutoramento
Vítor Félix
Professor Associado com Agregaçãoagradecimentos
We thank the EPSRC for a Ph.D. studentship for T.W. through the White Rose Life Science DTC. P.J.C. thanks FCT for the postdoctoral grant SFRH/BPD/27082/2006. V.F. acknowledges the funding from QREN-FEDER through the Operational Program Competitiveness Factors-COMPETE and National Funds through the FCT under project PTDC/QUI-QUI/101022/2008.