Computational strategies to model the interaction and the reactivity of biologically-relevant transition metal complexes
Abstract Transition metal atoms possess the unique capacity to induce significant changes in the electronic structure of their ligands, often culminating in substantial modification of their chemical behavior, and this ability explains well their evolutionary incorporation into the living matter. Exactly this complexity of metal atom behaviours on the electronic level is the reason of various quantum chemistry strategies have been developed for their description. On the other hand, the application of quantum chemistry methodologies to gain a comprehensive understanding of the interaction between metal and biological matter, can only be approached through adequate modelling of the chemical p…
Probing the Paradigm of Promiscuity for N‐Heterocyclic Carbene Complexes and their Protein Adduct Formation
Metal complexes can be considered a "paradigm of promiscuity" when it comes to their interactions with proteins. They often form adducts with a variety of donor atoms in an unselective manner. We have characterized the adducts formed between a series of isostructural N-heterocyclic carbene (NHC) complexes with Ru, Os, Rh, and Ir centers and the model protein hen egg white lysozyme by X-ray crystallography and mass spectrometry. Distinctive behavior for the metal compounds was observed with the more labile Ru and Rh complexes targeting mainly a surface l-histidine moiety through cleavage of p-cymene or NHC co-ligands, respectively. In contrast, the more inert Os and Ir derivatives were detec…
Two mixed valence diruthenium(ii,iii) isomeric complexes show different anticancer properties
In this paper it is demonstrated that the nature of the ligands of two Ru2(II,III) paddlewheel complexes dramatically affects the overall anticancer properties in cells. Herein, the complex [Ru2(EB776)4Cl] was found to be more active against a glioblastoma model with respect to its isomer [Ru2(EB106)4Cl]. These different effects depend on the steric hindrance, on the allowed conformations of the complexes and on the presence of hydrophilic regions in [Ru2(EB776)4Cl], which overall lead to a lower “steric protection”.
Multilayered Modelling of the Metallation of Biological Targets
The unique property of metals – the remarkable ability to modulate the electronic structure of both metal center and bound ligands – is the reason for their omnipresence in enzymes and in metal-coordinating biological factors. Modern metallodrug chemistry began with the serendipitous unveiling of the antitumour properties of cisplatin, followed by an avalanche of synthesized novel metallodrugs. The metallation of biological targets has then become a new paradigm in the field of bioinorganic chemistry, and a plethora of computational approaches have been developed and utilized to ease the detailed comprehension of its mechnisms with a focus on medical applications. Studies of the electronic …
Reaction of dirhodium and diruthenium paddlewheel tetraacetate complexes with nucleophilic protein sites: A computational study
Abstract The biomolecular affinity of three paddlewheel dinuclear complexes Rh2(µ-O2CCH3)4(H2O)2, Ru2(µ-O2CCH3)4(H2O)Cl, [Ru2(µ-O2CCH3)4(H2O)2]+ for the binding at cancer-specific protein targets was determined by means of DFT approaches. Thermodynamics of axial ligand substitution reaction by models of suitable protein sites was investigated in order to assess the binding selectivity displayed by the paddlewheel complexes. Both Rh2(µ-O2CCH3)4(H2O)2 and Ru2(µ-O2CCH3)4(H2O)Cl resulted to react favorably with most of the examined models of the protein side chains, with higher exergodicity demonstrated in the reaction of Arg, Cys, His, Lys, Sec, thus showing a limited selectivity. On the other…
Reactivity of antitumor coinage metal-based N-heterocyclic carbene complexes with cysteine and selenocysteine protein sites
Abstract The reaction of the antitumor M(I)-bis-N-heterocyclic carbene (M(I)-NHC) complexes, M = Cu, Ag, and Au, with their potential protein binding sites, i.e. cysteine and selenocysteine, was investigated by means of density functional theory approaches. Capped cysteine and selenocysteine were employed to better model the corresponding residues environment within peptide structures. By assuming the neutral or deprotonated form of the side chains of these amino acids and by considering the possible assistance of an external proton donor such as an adjacent acidic residue or the acidic component of the surrounding buffer environment, we devised five possible routes leading to the binding o…