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

Abstract

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.

Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects

“…Several mechanisms for peptide hydrolysis assisted by TM complexes have been proposed in the literature. − Most of them involve the initial coordination of the amide O atom of the peptide bond to the TM center that acts as a Lewis acid, activating the amide C atom toward a nucleophilic attack. However, they differ from each other in the way in which this nucleophilic attack occurs.…”

“…Previous computational studies on monometallic hydroxo complexes, − including cobalt and copper (oxa)­cyclen complexes, have assumed that the nucleophilic hydroxo ligand directly attacks the electrophilic carbonyl C atom. However, we noticed that for first-row TMs this process involves an unfavorable four-membered-ring transition state (Scheme , i–iv), which, in the case of cobalt­(III) and copper­(II) (oxa)­cyclen complexes, resulted in a high, computed energy barrier for hydrolysis of the Phe–Ala dipeptide bond, ca.…”

Application of Semiempirical Methods to Transition Metal Complexes: Fast Results but Hard-to-Predict Accuracy

“…8,[12][13][14][15][16][17][18][19][20] Numerous strategies have been proposed to overcome these issues, and many instructive results have been obtained. An 3 additional important challenge, the strong conformational flexibility of many TM species, has so far received only limited attention from selected research groups, [48][49][50][51][52][53][54][55][56][57][58] and is to large extent still an unsolved problem. This leads to known difficulties in the modeling of large TM complexes containing multiple rotatable bonds.…”

“…50,55,57,[71][72][73][74][75][76][77] Semiempirical methods [78][79][80][81] represent another out-of-the-box alternative to FF methods, albeit they are computationally more intensive, and have been successfully applied for decades in many areas of organic 78-79, 81-92 and to less extent transition metal chemistry. 33,36,45,[78][79] Thus, PM3(TM) and PM6 semiempirical methods have been successfully used for conformational search on molybdenum, [53][54] ruthenium, 116 rhenium 49 and technetium 51 systems. However, their accuracy 5 for relative conformational energies have never been systematically tested for a series systems containing various transition metals.…”

“…Transition metal (TM) complexes bearing large bulky ligands are examples of important catalysts, both in vivo and in the chemical and pharmaceutical industry. − To better understand their catalytic activity and physical properties, theoretical modeling of these complexes is today routinely undertaken and accounts for a significant fraction of the computational resources used worldwide. − The complex electronic structure of TM (which is responsible for their catalytic activity) implies a number of computational challenges for an accurate modeling, such as relativistic effects, dynamic and static correlation effects, poor scalability of the reliable theoretical methods, and multiple low-lying electronic states. ,− Numerous strategies have been proposed to overcome these issues, and many instructive results have been obtained. − An additional important challenge, the strong conformational flexibility of many TM species, has so far received only limited attention from selected research groups − and is to a large extent still an unsolved problem. This leads to known difficulties in the modeling of large TM complexes containing multiple rotatable bonds.…”