Theoretical Study of the Platinum Complexes Interactions with Sulfur-containing Amino Acids

 

Tomáš Zimmermann, Michal Zeizinger, and Jaroslav V. Burdaa

 

Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16 Prague 2, Czech Republic

 

Biologically important reactions of two cisplatin hydration products cis‑[Pt(NH3)2Cl(H2O)]+ and cis‑[Pt(NH3)2(OH)(H2O)]+ with sulfur-containing amino-acids cysteine and methionine were studied using density functional techniques. Considered reaction mechanism leads to formation of the chelated complexes where several monodentate intermediates were analyzed. Reaction energies were determined in the so-called supermolecule approach as well as in the non-interacting model (involving isolated molecules in reactant and product). First, all the structures were optimized using DFT method - B3LYP/6-31+G(d). For the optimized structures, single point calculations was done using slightly larger basis set (6-31++G**). Core electrons of platinum, sulfur and chlorine atoms were described by Stuttgart-Dresden pseudopotentials. Analysis of electronic density and partial charges (using NPA method) enabled a more detailed insight onto interaction energies.

In the first reaction step, the replacement of the aqua ligand was assumed where the monodentate Pt-(amino acid) was created. For the monohydrated complexes (with chloro-ligands), it was found that in cysteine-containing systems, a formation of sulfur bonded monodentate complexes is energetically preferred to formation of Pt-N and Pt-O bonds. On the other hand, the systems with methionine slightly favors a formation of nitrogen-bonded complexes to sulfur-bonded ones. The most stable conformer from the (dihydrated) hydroxo-complexes is structure where Pt-S bond was formed. Conformers with Pt-N bonds are slightly less stable for both amino acids. Structures with Pt-O bonds are the least favorable.

The next reaction step led to the chelate formation. This process is endotermic in case of chloro species and exotermic for hydoxo compounds in supermolecular approach. The most stable chelate structures contain k(N,S) binding sites.