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Investigation of the diverse evolutionary developed mechanisms enabling bacteria to maintain homeostasis and to be resistant to lead is crucial for the discovery of novel strategies for isolation of this highly toxic metal and its subsequent elimination from contaminated environments. The metalloregulatory protein pbrR and its homologues that were identified in the Cupriavidus metallidurans CH34 chromosome are the only characterized natural metalloproteins that have a special affinity toward Pb(II) and that bind it with at least a 1000-fold selectivity over other heavy metals. The X-ray structures of apo and Pb(II)-bound pbrR have been recently reported. In the present study, the binding of Pb(II) at pbrR was investigated by means of multiscale computational modeling. Molecular dynamics simulations substantiated how conformations amenable for the Pb(II) complexation through the tris-cysteine motif are formed from the antiparallel coiled-coil packing interaction of two dimerization helices of two pbrR monomers, and the phase space of apo-pbrR has been extensively sampled. Hybrid quantum mechanics/molecular mechanics (QM/MM) calculations on metal-bound structures of pbrR also allowed us to determine the most probable protonation state for the lead binding motif and evaluate the structural features mostly affecting the Pb(II) coordination in this protein. In agreement with available experimental data, we found that pbrR may control its Pb(II) affinity, probably, by conformational changes that affect the distance between Cys78' and Cys122 and their protonation states, thus being able to switch on the Pb(II) sequestration/release-prone states in response to external stimuli. The protein structure enveloping the metal binding motif favors the thiol-thiolate-thiolate protonation state of Pb(II)-pbrR, thus probably enhancing the binding selectivity for Pb(II), compared to other metal ions.

Several bacterial species have evolutionary developed protein systems specialized in the control of intracellular gold ion concentration. In order to prevent the detrimental consequences that may b...

The coordination of Pb(II) in aqueous solutions containing thiols is a pivotal topic to the understanding of the pollutant potential of this cation. Based on its hard/soft borderline nature, Pb(II) forms stable hydrated ions as well as stable complexes with the thiol groups of proteins. In this paper, the modeling of Pb(II) coordination via classical molecular dynamics simulations was investigated to assess the possible use of non-bonded potentials for the description of the metal–ligand interaction. In particular, this study aimed at testing the capability of cationic dummy atom schemes—in which part of the mass and charge of the Pb(II) is fractioned in three or four sites anchored to the metal center—in reproducing the correct coordination geometry and, also, in describing the hard/soft borderline character of this cation. Preliminary DFT calculations were used to design two topological schemes, PB3 and PB4, that were subsequently implemented in the Amber force field and employed in molecular dynamics simulation of either pure water or thiol/thiolate-containing aqueous solutions. The PB3 scheme was then tested to model the binding of Pb(II) to the lead-sensing protein pbrR. The potential use of CDA topological schemes in the modeling of Pb(II) coordination was here critically discussed.

Seven different density functionals, including GGAs, meta-GGAs, hybrids and range-separated hybrids, and considering Grimme’s empirical dispersion correction (M06-L, M06-2X, PBE0, B3LYP, B3LYP-D3, CAM-B3LYP, ωB97X) have been tested for their performance in the prediction of molecular structures, energies and energy barriers for a class of newly developed antitumor platinum complexes involving main group heavy elements such as arsenic. The calculated structural parameters, energies and energy barriers have been compared to the available experimental data. The results show that range-separated hybrid functionals CAM-B3LYP and ωB97X give good results in predicting both geometrical parameters and isomerization energies and barrier heights and are promising new tools for the theoretical study of novel platinum(II) arsenic compounds.

We carried out a detailed theoretical study on the mechanism of the carbene ligand substitution by cysteine and selenocysteine residues in an Au(I) bis-N-heterocyclic carbene complex in order to model the initial stages of the mechanism of action of this promising class of antitumor metallodrug. Both neutral and deprotonated capped Cys and Sec species were considered as possible nucleophiles in the ligand exchange reaction on the metal center to model the corresponding protein side chains. Energies and geometric structures of the possible transition states and reactant- and product-adducts involved in the substitution process have been calculated using density functional theory and local MP2. Reaction and activation enthalpies and free energies have been evaluated and indicate a slightly exothermic and exergonic process with reasonably low barriers, 21.3 and 19.6 kcal mol

Quite surprisingly, cisplatin and cis-[PtI2(NH3)2] were found to manifest significant differences in their reactions with the model protein lysozyme. We decided to explore whether these differences recur when reacting these two Pt compounds with other proteins. Notably, ESI-MS measurements carried out on cytochrome c nicely confirmed the reaction pattern observed for lysozyme. This prompted us to exploit a computational DFT approach to disclose the molecular basis of such behavior. We analyzed comparatively the reactions of cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] with appropriate molecular models (Ls) of the sidechains of relevant aminoacids. We found that when Pt(II) complexes are reacted with sulfur ligands both quickly lose their halide ligands and then the resulting cis-[Pt(L)2(NH3)2] species loses ammonia upon reaction with a ligand excess. In the case of imidazole, again cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] quickly lose their halide ligands but the resulting cis-[Pt(L)2(NH3)2] species does not lose ammonia by reaction with excess imidazole. These results imply that the two platinum complexes manifest a significantly different behavior in their reaction with representative small molecules in agreement with what observed in the case of model proteins. It follows that the protein itself must play a crucial role in triggering the peculiar reactivity of cis-[PtI2(NH3)2] and in governing the nature of the formed protein adducts. The probable reasons for the observed behavior are critically commented and discussed.

Au(PEt3)I (AF-I hereafter), the iodide analog of the FDA-approved drug auranofin (AF hereafter), is a promising anticancer agent that produces its pharmacological effects through interaction with non-genomic targets such as the thioredoxin reductase system. AF-I is endowed with a very favorable biochemical profile showing potent in vitro cytotoxic activity against several cancer types including ovarian and colorectal cancer. Remarkably, in a recent publication, some of us reported that AF-I induces an almost complete and rapid remission in an orthotopic in vivo mouse model of ovarian cancer. The cytotoxic potency does not bring about highly severe side effects, making AF-I very well-tolerated even for higher doses, even more so than the pharmacologically active ones. All these promising features led us to expand our studies on the mechanistic aspects underlying the antitumor activity of AF-I. We report here on an integrated experimental and theoretical study on the reactivity of AF-I, in comparison with auranofin, toward relevant aminoacidic residues or their molecular models. Results point out that the replacement of the thiosugar moiety with iodide significantly affects the overall reactivity toward the amino acid residues histidine, cysteine, methionine, and selenocysteine. Altogether, the obtained results contribute to shed light into the enhanced antitumoral activity of AF-I compared with AF.

Neutral N&ndash, heterocyclic carbene gold(I) compounds such as IMeAuCl are widely used both in homogeneous catalysis and, more recently, in medicinal chemistry as promising antitumor agents. In order to shed light on their reactivity with protein side chains, we have carried out density functional theory (DFT) calculations on the thermodynamics and kinetics of their reactions with water and various nucleophiles as a model of plausible protein binding sites such as arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, histidine, lysine, methionine, selenocysteine, and the N-terminal group. In agreement with recent experimental data, our results suggest that IMeAuCl easily interacts with all considered biological targets before being hydrated&mdash, unless sterically prevented&mdash, and allows the establishment of an order of thermodynamic stability and of kinetic reactivity for its binding to protein residues.

We carried out a theoretical study on the mechanism of electrochemical reduction of the prototypical platinum(IV) anticancer complex [Pt(NH3)2(CH3COO)2Cl2] to the corresponding platinum(II) [Pt(NH3...