Molecular Dynamics Studies of Changes in the DNA- Structure as Result of Interactions with Cisplatin

TL;DR

This study uses molecular dynamics simulations to observe how cisplatin binding induces significant conformational changes in DNA, transitioning from linear to bent structures similar to experimental observations.

Contribution

First real-time simulation demonstrating large DNA conformational changes induced by cisplatin adduct formation on nanosecond time scales.

Findings

Cisplatin causes DNA to bend and form cavities filled with solvent.

The transition from mono-adduct to bis-adduct structure occurs within 800 ps.

Stable bent DNA structure similar to experimental data is reached after 1300 ps.

Abstract

The 3'-monofunctional adduct of cisplatin and d(CTCTG*G*TCTC)2 duplex DNA in solvent with explicit counter ions and water molecules were subjected to MD- simulation with AMBER force field on a nanosecond time scale. In order to simulate the closure of the bond between the Pt and 5'-guanine-N7 atoms, the forces acting between them were gradually increased during MD. After 500-800 ps the transformation of the mono-adduct (straight DNA with the cisplatin residue linked to one guanine-N7) to the bus-adduct (bent DNA where Pt atom is connected through the N7 atoms of neighboring guanines) was observed. A cavity between palatinate guanines is formed and filled with solvent molecules. The rapid inclination of the center base pairs initiates a slow transition of the whole molecule from the linear to the bent conformation. After about 1000-1300 ps a stable structure was reached, which is very similar to the one described experimentally. The attractive force between the Pt- atom and the N7 of the second guanine plays the main role in the large conformational changes induced by formation of the adduct-adduct. X-N-Pt-N-torsions accelerate the bending but a torsion force constant greater than 0.2 Kcal/mol lead to the breaking of the H-bonds within the base pairs. The present study is the first dynamical simulation that demonstrates in real time scale such a large conformational perturbation of DNA.