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Thesis

Université Paris V - René Descartes

Friday 31 August 2012, by Stéphane Téletchéa

All the versions of this article: [English] [français]

«Etude par modélisation de dynamique moléculaire et spectroscopie RMN des déformations induites par la coordination du cisplatine sur l’ADN»

Abstract :

Cisplatin (cis-diammin dichloro platin) is one of the most widely used anti cancer chemotherapy drug. Its anticancer activity has been first described in 1965 by B. Rosenberg. Since then, many studies have been undertaken to decipher its mechanism of action.

From an original approach linking molecular dynamics simulation and experimental studies, my PhD allowed a dynamic description of a platinated adduct on the sequence 5’ -GCCG*G*GTCGC- 3’ / 5’ -GCGACCCGGC- 3’ (where G* is a platinated guanine). The resulting structure has been studied previously in our laboratory on the identical sequence but with an A-T base pair on the 3’ side of the platinated guanines (subsequently named G*G*A). Therefore we studied the structural implications of an A to G substition in the 3’ region on the adduct structure. This is the first structural study on a cisplatin adduct containing three adjacent guanines. GGG sequences and Gn (n≥3) are known to be favored targets for platin (II) but their adducts have not been studied by NMR since their purification are problematic.

This G*G*G NMR study has been compared to its dynamics simulation, where the parm 98 force field has been specifically optimized for taking into account the platin coordination sphere. The parametrisation has been cross-validated by the NMR experiment.

To calculate the proportion of BI/BII DNA substates, a novel method has been set up. Four distances, namely H2’’(n)-H8(n), H1’(n)-H6/8(n+1), H2’(n)-H6/8(n+1) and H2’’(n)-H6/8(n+1) allow to discriminate between the two substates and to calculate the proportion of each substate.

The force field optimizations and the BI/BII DNA substates discrimination method allowed a precise description of the cisplatin-DNA adduct, allowing to study one possible way of anti-cancer efficiency. The complex cisplatin-DNA-Protein (notably LEF I - Lymphoïd Enhanced Factor I) is a plausible candidate to explain why the cancerous cell elects apoptosis or tumor repair. The protein-DNA (without cisplatin) ensemble simulation has allowed to describe the recognition path of the DNA deformation by the protein and the implication of a water molecule in the recognition mechanism.

All these studies on cisplatin-DNA allowed us to get enough knowledge on the resulting deformations. Therefore, we then studied the structural deformation induced by another platin-related complex, the pyrazolate-bis-platine. This complex has been designed to obtain a small DNA deformation, in order to get a different response than the one of cisplatin. The molecular dynamics simulation has indicated it induces a smaller kink and a different global deformation than cisplatin, thus proving a different recognition mode. Since it is known by in vitro studies that the pyrazolate-bis-platine owns an anti-tumoral activity, the dynamics simulations suggest its cellular mechanism is different than the one of cisplatin.

These PhD studies have allowed a better understanding of DNA-cisplatin, DNA-cisplatin-protein dynamic description and to improve the definition of platinated complex for force fields parm 98 (and parm 99) of the molecular dynamics simulation suite AMBER.

Thèse de doctorat
Mémoire de thèse pour l’obtention du doctorat de l’université Paris V, mention Très Honorable avec Félicitations du Jury

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