Giuseppe Sciortino

Prediction of the interaction of metallic moieties with proteins: An update for protein-ligand docking techniques

In this article, we present a new approach to expand the range of application of protein‐ligand docking methods in the prediction of the interaction of coordination complexes (i.e., metallodrugs, natural and artificial cofactors, etc.) with proteins. To do so, we assume that, from a pure computational point of view, hydrogen bond functions could be an adequate model for the coordination bonds as both share directionality and polarity aspects. In this model, docking of metalloligands can be performed without using any geometrical constraints or energy restraints. The hard work consists in generating the convenient atom types and scoring functions. To test this approach, we applied our model to 39 high‐quality X‐ray structures with transition and main group metal complexes bound via a unique coordination bond to a protein. This concept was implemented in the protein‐ligand docking program GOLD. The results are in very good agreement with the experimental structures: the percentage for which the RMSD of the simulated pose is smaller than the X‐ray spectra resolution is 92.3% and the mean value of RMSD is < 1.0 Å. Such results also show the viability of the method to predict metal complexes–proteins interactions when the X‐ray structure is not available. This work could be the first step for novel applicability of docking techniques in medicinal and bioinorganic chemistry and appears generalizable enough to be implemented in most protein‐ligand docking programs nowadays available.

Elucidation of Binding Site and Chiral Specificity of Oxidovanadium Drugs with Lysozyme through Theoretical Calculations

This study presents an implementation of the protein-ligand docking program GOLD and a generalizable method to predict the binding site and orientation of potential vanadium drugs. Particularly, theoretical methods were applied to the study of the interaction of two VIVO complexes with antidiabetic activity, [VIVO(pic)2(H2O)] and [VIVO(ma)2(H2O)], where pic is picolinate and ma is maltolate, with lysozyme (Lyz) for which electron paramagnetic resonance spectroscopy suggests the binding of the moieties VO(pic)2 and VO(ma)2 through a carboxylate group of an amino acid residue (Asp or Glu). The work is divided in three parts: (1) the generation of a new series of parameters in GOLD program for vanadium compounds and the validation of the method on five X-ray structures of VIVO and VV species bound to proteins; (2) the prediction of the binding site and enantiomeric preference of [VO(pic)2(H2O)] to lysozyme, for which the X-ray diffraction analysis displays the interaction of a unique isomer (i.e., OC-6-23-Δ) through Asp52 residue, and the subsequent refinement of the results with quantum mechanics/molecular mechanics methods; (3) the application of the same approach to the interaction of [VO(ma)2(H2O)] with lysozyme. The results show that convenient implementation of protein-ligand docking programs allows for satisfactorily reproducing X-ray structures of metal complexes that interact with only one coordination site with proteins and predicting with blind procedures relevant low-energy binding modes. The results also demonstrate that the combination of docking methods with spectroscopic data could represent a new tool to predict (metal complex)-protein interactions and have a general applicability in this field, including for paramagnetic species.

GaudiMM: A modular multi-objective platform for molecular modeling

GaudiMM (for Genetic Algorithms with Unrestricted Descriptors for Intuitive Molecular Modeling) is here presented as a modular platform for rapid 3D sketching of molecular systems. It combines a Multi‐Objective Genetic Algorithm with diverse molecular descriptors to overcome the difficulty of generating candidate models for systems with scarce structural data. Its grounds consist in transforming any molecular descriptor (i.e. those generally used for analysis of data) as a guiding objective for PES explorations. The platform is written in Python with flexibility in mind: the user can choose which descriptors to use for each problem and is even encouraged to code custom ones. Illustrative cases of its potential applications are included to demonstrate the flexibility of this approach, including metal coordination of multidentate ligands, peptide folding, and protein‐ligand docking. GaudiMM is available free of charge from https://github.com/insilichem/gaudi.

Decoding Surface Interaction of V IV O Metallodrug Candidateswith Lysozyme

The interaction of metallodrugs with proteins influences their transport, uptake, and mechanism of action. In this study, we present an integrative approach based on spectroscopic (EPR) and computational (docking) tools to elucidate the noncovalent binding modes of various VIVO compounds with lysozyme, a prototypical model of protein receptor. Five VIVO-flavonoid drug candidates formed by quercetin (que), morin (mor), 7,8-dihydroxyflavone (7,8-dhf), chrysin (chr), and 5-hydroxyflavone (5-hf)-effective against several osteosarcoma cell lines-and two benchmark VIVO species of acetylacetone (acac) and catechol (cat) are evaluated. The results show a gradual variation of the EPR spectra at room temperature, which is associated with the strength of the interaction between the square pyramidal complexes [VOL2] and the surface residues of lysozyme. The qualitative strength of the interaction from EPR is [VO(que)2]2- ≈ [VO(mor)2] > [VO(7,8-dhf)2]2- > [VO(chr)2] ≈ [VO(5-hf)2] > [VO(acac)2] ≈ [VO(cat)2]2-. This observation is compared with protein- ligand docking calculations with GOLD software examining the GoldScore scoring function ( F), for which hydrogen bond and van der Waals contact terms have been optimized to account for the surface interaction. The best predicted binding modes display an energy trend in good agreement with the EPR spectroscopy. Computation indicates that the strength of the interaction can be predicted by the Fmax value and depends on the number of OH or CO groups of the ligands that can interact with different sites on the protein surface and, more particularly, with those in the vicinity of the active site of the enzyme. The interaction strength determines the type of signal revealed ( rigid limit, slow tumbling, or isotropic) in the EPR spectra. Spectroscopic and computational results also suggest that there are several sites with comparable binding energy, with the V complexes distributing among them in a bound state and in aqueous solution in an unbound state. This kind of study and analysis could be generalized to determine the noncovalent binding modes of a generic metal species with a generic protein.

Iridium-Catalyzed Isomerization of N-Sulfonyl Aziridines to Allyl Amines

The Crabtrees reagent catalyzes the isomerization of N-sulfonyl 2,2-disubstituted aziridines to allyl amines. The selectivity of allyl amine vs imine is very high (up to 99/1). The unprecedented isomerization takes place in mild conditions without activation of the catalyst by hydrogen. The mechanism has been studied computationally by DFT calculations; instead of the usual hydrogenation of COD, the catalytic species is formed by a loss of the pyridine ligand. Approaching of aziridine to this unsaturated species leads to a carbocation intermediate through a low energy barrier. A metal-mediated tautomerization involving sequentially γ-H elimination and N-H reductive elimination affords selectively the allyl amine. The readiness of the CγH bond to participate in the H elimination step accounts for the selectivity toward the allyl amine product.

Directed self-assembly of trimeric DNA-binding chiral miniprotein helicates

We propose that peptides are highly versatile platforms for the precise design of supramolecular metal architectures, and particularly, for the controlled assembly of helicates. In this context, we show that the bacteriophage T4 Fibritin foldon (T4Ff) can been engineered on its N-terminus with metal-chelating 2,2′-bipyridine units that stereoselectively assemble in the presence of Fe(II) into parallel, three-stranded peptide helicates with preferred helical orientation. Modeling studies support the proposed self-assembly and the stability of the final helicate. Furthermore, we show that these designed mini-metalloproteins selectively recognize three-way DNA junctions over double-stranded DNA.