Kinetics of Reactions of Dirhodium and Diruthenium Paddlewheel Tetraacetate Complexes with Nucleophilic Protein Sites: Computational Insights

Recently, dirhodium and diruthenium paddlewheel complexes have drawn attention as perspective anticancer drugs. In this study, the kinetics of reaction of typical paddlewheel scaffolds Rh2(μ-O2CCH3)4(H2O)2, Ru2(μ-O2CCH3)4(H2O)Cl, and [Ru2(μ-O2CCH3)4(HO)Cl]− with protein nucleophiles were investigated by means of the density functional theory. The substitution of axial ligandswater and chlorideby the models of protein residue side chains was analyzed, revealing the binding selectivity displayed by these paddlewheel metal scaffolds. The substitution of water is under a thermodynamic control, in which, although the Arg, Cys–, and Sec– residues are the most favorable, their binding is expected to be scarcely selective in a biological context. On the other hand, the replacement of the axial water with a more stable hydroxo ligand induces the chloride substitution in diRu complexes, which also targets Arg, Cys–, and Sec–, although with a moderately higher activation barrier for any examined protein residue. Additionally, the carried out characterization of the geometrical parameters of the transition states permitted determination of the impact of an increased steric hindrance of diRh and diRu complexes on their protein site selectivity. This study corroborates the idea of the substitution of the acetate ligands with biologically active, but more hindering, carboxylate ligands, in order to yield dual acting metallodrugs. This study allows us to assume that the delivery of diRu paddlewheel complexes in their monoanionic form [Ru2(μ-O2CR)4(OH)Cl]− decorated by the bulky substituents R may constitute an approach to augment the selectivity toward anticancer targets, such as TrxR in tumor cells, although under the condition that such a selectivity is operative only in high pH conditions

Effects of Terminal Substituents on Metallacumulene Complexes: A Density Functional Study on (CO)₅Cr(C)<i>_n</i>X₂ (X=F, SiH₃, CHCH₂, NH₂, NO₂)

Density functional calculations have been carried out on the series of metallacumulene complexes [(CO)5Cr(C)nX2)] (X = F, SiH3, CHCH2, NH2, NO2; n = 2−8) to study the effects of the terminal substituents on electronic structure, bonding, and reactivity of these complexes based on d6 transition metal fragments. Optimized geometries have been calculated for all complexes and found in good agreement with the available X-ray experimental data. The calculated dissociation energies for the metal−cumulene bond are significantly affected mainly by the NH2 and NO2 substituents acting by resonance effect. In particular the π-donor amino substituents cause a decrase while the π-acceptor nitro substituents cause an increase of the bonding energies which are more evident for cumulenes with an odd or an even number of carbon atoms, respectively. The electronic structure has been analyzed in terms of the synergistic σ donation π back-donation model and the contribution from π back-donation was found much more sensitive to the nature of the substituents. The perturbational theory of reactivity has been employed to explain the effect of the substituents on reactivity patterns of these complexes

Reactivity of N‑Heterocyclic Carbene Half-Sandwich Ru‑, Os‑, Rh‑, and Ir-Based Complexes with Cysteine and Selenocysteine: A Computational Study

The structure and the reactivity of four half-sandwich metal complexes of RuII, OsII, RhIII, and IrIII were investigated by means of density functional theory approaches. These piano-stool complexes, grouped in cym-bound complexes, RuII(cym)­(dmb)­Cl2, 1, and OsII(cym)­(dmb)­Cl2, 2, and Cp*-bound complexes, RhIII(Cp*)­(dmb)­Cl2, 3, and IrIII(Cp*)­(dmb)­Cl2, 4, with cym = η6-p-cymene, Cp* = η5-pentamethylcyclopentadienyl, and dmb = 1,3-dimethylbenzimidazol-2-ylidene, were recently proposed as anticancer metallodrugs that preferably target Cys- or Sec-containing proteins. Thus, density functional theory calculations were performed here to characterize in detail the thermodynamics and the kinetics underlining the targeting of these metallodrugs at either neutral or anionic Cys and Sec side chains. Calculations evidenced that all these complexes preferably target at Cys or Sec via chloro exchange, although cym-bound and Cp*-bound complexes resulted to be more prone to bind at neutral or anionic forms, respectively, of these soft protein sites. Further decomposition analyses of the activation free energies for the reaction between 1–4 complexes and either Cys or Sec, paralleled with the comparison among the optimized transition-state structures, allowed us to spotlight the significant role played by solvation in determining the overall reactivity and selectivity expected for these prototypical metallodrugs

Ca²⁺-mediatedaggregation of PrP^C units.

Hypotheses drawn for the reaction of DBM with free or [Ca(H2O)5]2+-coordinated CH3CH2COO- (reaction (1) and (2), respectively), and reaction of [Ca(H2O)5(CH3CH2COO)]+ with CH3CH2COO- (3). Reduced model of DBM was obtained by replacing Ser 231, Asp 167, and Glu 168 labels with the corresponding aminoacid scaffold in the capped form: N-acetyl and methylamide form of N and C terminus, respectively. Monocoordinated Ca2+-binding sites were modelled by CH3CH2COO-.</p

MEP similarity.

Profiles of Carbò index compared each PrP system versus I (A-B) and II (C-D) systems. The reported IIIa and IIIb profiles were obtained by averaging IIIa1\IIIa2 and IIIb1\IIIb2 profiles, respectively.</p

Metal Fragment Modulation of Metallacumulene Complexes: A Density Functional Study

Density functional calculations have been carried out on a series of metallacumulene complexes LmM(C)nH2 with several MLm metal fragments to study the electronic structure, the bonding, and the reactivity of these complexes and how they are affected by the metal termini. The considered metal fragments include [(Cp)2(PH3)Ti], [Cp(PH3)2Mo]+, [(CO)5Cr], [(CO)5Mo], [(CO)5W], [Cp(dppe)Fe]+, [trans-Cl(dppe)2Ru]+, [Cp(PMe3)2Ru]+, [BzCl(PH3)Ru]+, [trans-Cl(PH3)2Rh], and [trans-Cl(PH3)2Ir], which are quite common in the chemistry of metal vinylidene, allenylidene, and higher cumulenes and range from a d2 to a d8 configuration and from electron-poor to electron-rich character. The optimized geometries calculated for the considered complexes have been found to be in good agreement with the available X-ray data and show that the peculiar carbon−carbon bond alternation superimposed to an average cumulenic structure, which is typical of these systems, is slightly perturbed by the nature of the metal fragment with the exception of the d4 [Cp(PH3)2Mo]+. Bonding energies have been calculated for all considered systems, and their dependence on the nature of the metal termini has been discussed. In particular an increase of the electron richness within d6 metal fragments causes a slight decrease of metal−cumulene bond energy. On the other hand, bond energies for d8 and, to a lesser extent, d4−d2 complexes are larger than those for the d6 analogues. The charge distribution and the localization of the molecular orbitals have been employed to explain the known reactivity patterns of this class of complexes and to forecast their variation with the nature of the metal fragment for both even and odd chains

Dissociative Route to C−H Bond Activation: DFT Study of Ligand Cyclometalation in a Platinum(II) Complex

Density functional calculations have been carried out on the cycloplatination reaction of cis-[Pt(Me)2(dmso)(P(o-tol)3)] (1) leading to the C,P-cyclometalated compound [Pt{CH2C6H4P(o-tolyl)2-κC,P}(Me)(dmso)] (6) with liberation of methane. Our calculations have confirmed that this reaction develops along a multistep mechanism consisting of (i) reversible dissociation of the dmso ligand to give the coordinatively unsaturated 14-electron T-shaped intermediate [Pt(Me)2(P(o-tol)3)] (2), (ii) intramolecular oxidative addition of the C−H bond of a methyl group on the P(o-tol)3 ligand to give the pentacordinate cyclometalated hydride species 3, (iii) reductive elimination of methane to give the σ-complex 4, which evolves to the unsaturated 14-electron species 5, and (iv) fast reassociation of the dmso ligand to give the final C,P-cyclometalated square-planar product 6, allowing also for an evaluation of the energies and a better understanding of the bonding and structural features of the species intercepted along the potential energy surface (PES) of the reaction

Simplified scheme of the formation of PrP aggregates.

<p>Simplified scheme of the formation of PrP aggregates.</p

Structural Reshaping of the Zinc-Finger Domain of the SARS-CoV‑2 nsp13 Protein Using Bismuth(III) Ions: A Multilevel Computational Study

The identification of novel therapeutics against the pandemic SARS-CoV-2 infection is an indispensable new address of current scientific research. In the search for anti-SARS-CoV-2 agents as alternatives to the vaccine or immune therapeutics whose efficacy naturally degrades with the occurrence of new variants, the salts of Bi3+ have been found to decrease the activity of the Zn2+-dependent non-structural protein 13 (nsp13) helicase, a key component of the SARS-CoV-2 molecular tool kit. Here, we present a multilevel computational investigation based on the articulation of DFT calculations, classical MD simulations, and MIF analyses, focused on the examination of the effects of Bi3+/Zn2+ exchange on the structure and molecular interaction features of the nsp13 protein. Our calculations confirmed that Bi3+ ions can replace Zn2+ in the zinc-finger metal centers and cause slight but appreciable structural modifications in the zinc-binding domain of nsp13. Nevertheless, by employing an in-house-developed ATOMIF tool, we evidenced that such a Bi3+/Zn2+ exchange may decrease the extension of a specific hydrophobic portion of nsp13, responsible for the interaction with the nsp12 protein. The present study provides for a detailed, atomistic insight into the potential anti-SARS-CoV-2 activity of Bi3+ and, more generally, evidences the hampering of the nsp13–nsp12 interaction as a plausible therapeutic strategy

The Effects of Ca²⁺ Concentration and E200K Mutation on the Aggregation Propensity of PrP^C: A Computational Study

<div><p>The propensity of cellular prion protein to aggregation is reputed essential for the initiation of the amyloid cascade that ultimately lead to the accumulation of neurotoxic aggregates. In this paper, we extended and applied an already reported computational workflow [Proteins 2015; 83: 1751–1765] to elucidate in details the aggregation propensity of PrP protein systems including wild type, wild type treated at different [Ca²⁺] and E200K mutant. The application of the computational procedure to two segments of PrP^C, i.e. 125–228 and 120–231, allowed to emphasize how the inclusion of complete C-terminus and last portion (120–126) of the neurotoxic segment 106–126 may be crucial to unveil significant and unexpected interaction properties. Indeed, the anchoring of N-terminus on H2 domain detected in the wild type resulted to be disrupted upon either E200K mutation or Ca²⁺ binding, and to unbury hydrophobic spots on the PrP^C surface. A peculiar dinuclear Ca²⁺ binding motif formed by the C-terminus and the S2-H2 loop was detected for [Ca²⁺] > 5 mM and showed similarities with binding motifs retraced in other protein systems, thus suggesting a possible functional meaning for its formation. Therefore, we potentiated the computational procedure by including a tool that clusterize the minima of molecular interaction fields of a proteinand delimit the regions of space with higher hydrophobic or higher hydrophilic character, hence, more likely involved in the self-assembly process. Plausible models for the self-assembly of either the E200K mutated or Ca²⁺-bound PrP^C were sketched and discussed. The present investigation provides for structure-based information and new prompts that may represent a starting point for future experimental or computational works on the PrP^C aggregation.</p></div