ESIgen: Electronic Supporting Information Generator for Computational Chemistry Publications

Electronic supporting information (ESI) occupies a fundamental position in the way scientists report their work. It is a key element in lightening the writing of the core manuscript and makes concise communication easier for the authors. Computational chemistry, as all fields related to structural studies of molecules, tends to generate huge amounts of data that should be inserted in the ESI. ESI reports originating from computational chemistry works generally reach tens of sheets long and include 3D depictions, coordinates, energies, and other characteristics of the structures involved in the molecular process understudy. While most experienced users end up building scripts that dig throughout the output files searching for the relevant data, this is not the case for users without programming experience or time. Here we present an automated ESI generator supported by both web-based and command line interfaces. Focused on quantum mechanics calculations outputs so far, we trust that the community would find this tool useful. Source code is freely available at https://github.com/insilichem/esigen. A web app public demo can be found at http://esi.insilichem.com

Decoding Surface Interaction of V^IVO Metallodrug Candidates with 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 V^IVO compounds with lysozyme, a prototypical model of protein receptor. Five V^IVO-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 V^IVO 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-<i>ligand</i> docking calculations with GOLD software examining the GoldScore scoring function (<i>F</i>), 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 <i>F</i>_max 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 (<i>rigid limit</i>, <i>slow tumbling</i>, or <i>isotropic</i>) 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

3D Structures and Redox Potentials of Cu²⁺–Aβ(1–16) Complexes at Different pH: A Computational Study

Oxidative stress induced by redox-active metal cations such as Cu²⁺ is a key event in the development of Alzheimer’s disease. A detailed knowledge of the structure of Cu²⁺–Aβ complex is thus important to get a better understanding of this critical process. In the present study, we use a computational approach that combines homology modeling with quantum-mechanics-based methods to determine plausible 3D structures of Cu²⁺–Aβ­(1–16) complexes that enclose the different metal coordination spheres proposed experimentally at different pH values. With these models in hand, we determine their standard reduction potential (SRP) with the aim of getting new insights into the relation between the structure of these complexes and their redox behavior. Results show that in all cases copper reduction induces CO_backbone decoordination, which, for distorted square planar structures in the oxidized state (Ia_δδ, IIa_εδε, IIa_εεε, and IIc_ε), leads to tricoordinated species. For the pentacoordinated structural candidate Ib_δε with Glu11 at the apical position, the reduction leads to a distorted tetrahedral structure. The present results highlight the importance of the nature of the ligands on the SRP. The computed values (with respect to the standard hydrogen electrode) for complexes enclosing negatively charged ligands in the coordination sphere (from −0.81 to −0.12 V) are significantly lower than those computed for models involving neutral ligands (from 0.19 to 0.28 V). Major geometry changes induced by reduction, on both the metal site and the peptide configuration, are discussed as well as their possible influence in the formation of reactive oxygen species

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 V^IVO complexes with antidiabetic activity, [V^IVO­(pic)₂(H₂O)] and [V^IVO­(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 V^IVO and V^V 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

Synthesis of Novel Nucleoside Analogues Built on a Bicyclo[4.1.0]heptane Scaffold

A new class of carbocyclic nucleoside analogues built on a bicyclo[4.1.0]­heptane scaffold, a perspective novel pseudosugar pattern, have been conceived as anti-HSV agents on the basis of initial protein–ligand docking studies. The asymmetric synthesis of a series of these compounds incorporating different nucleobases has been efficiently completed starting from 1,4-cyclohexanedione

Structural, Kinetic, and Docking Studies of Artificial Imine Reductases Based on Biotin–Streptavidin Technology: An Induced Lock-and-Key Hypothesis

An artificial imine reductase results upon incorporation of a biotinylated Cp*Ir moiety (Cp* = C₅Me₅^–) within homotetrameric streptavidin (Sav) (referred to as Cp*Ir­(Biot-<i>p</i>-L)­Cl] ⊂ Sav). Mutation of S112 reveals a marked effect of the Ir/streptavidin ratio on both the saturation kinetics as well as the enantioselectivity for the production of salsolidine. For [Cp*Ir­(Biot-<i>p</i>-L)­Cl] ⊂ S112A Sav, both the reaction rate and the selectivity (up to 96% ee (<i>R</i>)-salsolidine, <i>k</i>_cat 14–4 min^–1 vs [Ir], <i>K</i>_M 65–370 mM) decrease upon fully saturating all biotin binding sites (the ee varying between 96% ee and 45% ee <i>R</i>). In contrast, for [Cp*Ir­(Biot-<i>p</i>-L)­Cl] ⊂ S112K Sav, both the rate and the selectivity remain nearly constant upon varying the Ir/streptavidin ratio [up to 78% ee (<i>S</i>)-salsolidine, <i>k</i>_cat 2.6 min^–1, <i>K</i>_M 95 mM]. X-ray analysis complemented with docking studies highlight a marked preference of the S112A and S112K Sav mutants for the <i>S</i>_Ir and <i>R</i>_Ir enantiomeric forms of the cofactor, respectively. Combining both docking and saturation kinetic studies led to the formulation of an enantioselection mechanism relying on an “induced lock-and-key” hypothesis: the host protein dictates the configuration of the biotinylated Ir-cofactor which, in turn, by and large determines the enantioselectivity of the imine reductase