Molecular Modeling of Bioorganometallic Compounds: Thermodynamic Properties of Molybdocene–Glutathione Complexes and Mechanism of Peptide Hydrolysis

The computational study of bioinorganic complexes between transition metals and flexible ligands is still challenging, given that, besides requiring extensive conformational searches, the treatment of metal–ligand bonds demands the application of quantum chemical methods. Herein, the adducts formed between molybdocene, which exhibits antitumor activity and reacts with thiol groups to give stable water‐soluble complexes, and the tripeptide glutathione, which is a major source of biological thiols, are studied. Conformational searches are performed using the semiempirical PM6 method followed by geometry optimizations and single‐point calculations using density functional theory methods. In addition, molecular dynamics simulations of the molybdocene–glutathione complex involved in the regioselective hydrolysis of the Cys–Gly linkage are performed in explicit solvent. The reactive process is also studied theoretically on cluster models of both the molybdocene‐bound and the free peptide.