Atomic level rendering of DNA-drug encounter.

Computer simulations have been demonstrated to be important for unraveling atomic mechanisms in biological systems. In this study, we show how combining unbiased molecular dynamic simulations with appropriate analysis tools can successfully describe metal-based drug interactions with DNA. To elucidate the noncovalent affinity of cisplatin's family to DNA, we performed extensive all-atom molecular dynamics simulations (3.7 µs total simulation length). The results show that the parent drug, cisplatin, has less affinity to form noncovalent adducts in the major groove than its aquo complexes. Furthermore, the relative position in which the drugs enter the major groove is dependent on the compound's net charge. Based on the simulations, we estimated noncovalent binding free energies through the use of Markov state models. In addition, and to overcome the lack of experimental information, we employed two additional methods: Molecular Mechanics Poisson-Boltzmann Surface Area (MMPB-SA) and steered molecular dynamics with the Jarzynski estimator, with an overall good agreement between the three methods. All complexes show interaction energies below 3 kcal/mol with DNA but the charged hydrolysis products have slightly more favorable binding free energies than the parent drug. Moreover, this study sets the precedent for future unbiased DNA-ligand simulations of more complex binders.

The degradation pathways in chloride medium of the third generation anticancer drug oxaliplatin.

We have investigated the degradation reactions, in chloride medium, of the third generation drug oxaliplatin using density functional theory. Our calculations confirm that this drug should be administered in chloride free solutions, and we have ascertained the main biodegradation products upon chloride binding, which are essential to establish the active compounds reacting with DNA. In addition, detailed knowledge of these platinum complexes is fundamental for correct elimination procedures in wastewater treatments.

On the Nature of the CP Bond in Phosphaalkynes.

In this work, we report results of calculations based on the density functional theory (B3LYP/6-311+G(2d,2p)) of different species containing a terminal cyaphide bond. The chosen species range from small molecules and anions (C⋮P(-), HC⋮P, tBuC⋮P, [(CF3)3BC⋮P)](-)) to large transition-metal containing complexes ([(dppe)2Ru(H)(C⋮P)], trans-[Pt(PMe3)2(Cl)(C⋮P)], trans-[Pt(PMe3)2(Cl)(CP)Pt(PMe3)2]). A comparative analysis of the description of the C⋮P bond obtained by different methodologies is presented. Topological analyses of the electron density in the framework of the theory of atoms in molecules (AIM) and of the electron localization function (ELF) are complemented with the results obtained by natural bond orbital analysis (NBO).