Pyteomics—a Python Framework for Exploratory Data Analysis and Rapid Software Prototyping in Proteomics

Pyteomics is a cross-platform, open-source Python library providing a rich set of tools for MS-based proteomics. It provides modules for reading LC-MS/MS data, search engine output, protein sequence databases, theoretical prediction of retention times, electrochemical properties of polypeptides, mass and m/z calculations, and sequence parsing. Pyteomics is available under Apache license; release versions are available at the Python Package Index http://pypi.python.org/pyteomics, the source code repository at http://hg.theorchromo.ru/pyteomics, documentation at http://packages.python.org/pyteomics. Pyteomics.biolccc documentation is available at http://packages.python.org/pyteomics.biolccc/. Questions on installation and usage can be addressed to pyteomics mailing list: pyteomics@googlegroups.com      

A novel calix[4]arene-based neutral semicarbazone receptor for anion recognition

A series of novel calix[4]arene-based neutral semicarbazone and thiosemicarbazone receptors have been synthesized and characterized. The molecular receptor 4a recognizes in preference to other anions (Cl⁻, Br⁻, I⁻, , and ) through a 1:1 binding-stoichiometry.     

Assessing the similarity of ligand binding conformations with the Contact Mode Score

Structural and computational biologists often need to measure the similarity of ligand binding conformations. The commonly used root-mean-square deviation (RMSD) is not only ligand-size dependent, but also may fail to capture biologically meaningful binding features. To address these issues, we developed the Contact Mode Score (CMS), a new metric to assess the conformational similarity based on intermolecular protein-ligand contacts. The CMS is less dependent on the ligand size and has the ability to include flexible receptors. In order to effectively compare binding poses of non-identical ligands bound to different proteins, we further developed the eXtended Contact Mode Score (XCMS). We believe that CMS and XCMS provide a meaningful assessment of the similarity of ligand binding conformations. CMS and XCMS are freely available at http://brylinski.cct.lsu.edu/content/contact-mode-score and http://geaux-computational-bio.github.io/contact-mode-score/.     

Syntheses, crystal structure and properties of two novel coordination polymers with the flexible tetrazole-1-acetic acid (Htza)

Two new coordination polymers, [Ag(tza)]_∞ (1) (Htza=tetrazole-1-acetic acid) and [Cu(tza)₂]_∞ (2) have been prepared at room temperature and characterized by X-ray crystallography, IR, UV-vis, fluorescence spectra and magnetism analysis. Compound 1 exhibits extended helical chains through bridging ligand tza. The AgAg interactions between the adjacent chains form a 3-D framework featuring the extended tza-connected Ag chains that obviously affect the photoluminescent property. Compound 2 features undulated layered structure with hourglass-shaped [Cu₄(tza)₄] as subunits with the weak ferromagnetic interactions between Cu(II) ions, which are further stabilized by inter-lamellar CHO hydrogen bonds in the resulting 3-D supramolecular framework.     

Redox responsive molecular tweezers with tetrathiafulvalene units: synthesis, electrochemistry, and binding properties

Several new molecular tweezers with tetrathiafulvalene (TTF) arms as well as mono-TTF derivatives bearing 3,5-di-tert-butylbenzylthio groups to provide enhanced solubility were prepared starting from a bis-cyanoethyl-protected tetrathiafulvalene derivative. The X-ray crystallographic analysis of 3 and 7a showed highly distorted TTF groups and absence of close TTF-TTF contacts in the crystalline state. Comparative cyclic voltammetry (CV) measurements demonstrated that through space distance-dependent TTF-TTF interactions take place in the TTF-containing molecular tweezers, leading to electronic pairing with formation of mixed valence [TTF]₂⁺ species and splitting of the first oxidation wave. TTF-containing molecular tweezers were successfully tested as receptors for several electron-deficient substances.     

Mapping Receptor Density on Live Cells by Using Fluorescence Correlation Spectroscopy

Sensitive surveying : Fluorescence correlation spectroscopy (FCS) was used to study receptor density and to monitor ligand–receptor interactions on live cell membranes by the introduction of fluorescently marked aptamers, which specifically bind to certain cell‐surface receptors (see schematic representation; FITC: fluorescein isothiocyanate).

     

TargetNet: a web service for predicting potential drug–target interaction profiling via multi-target SAR models

Drug–target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug–drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user’s molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75–100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug–drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.     

Columnar Aggregates of Azobenzene Stars: Exploring Intermolecular Interactions,Structure, and Stability in Atomistic Simulations

We present a simulation study of supramolecular aggregates formed by three-arm azobenzene (Azo) stars with a benzene-1,3,5-tricarboxamide (BTA) core in water. Previous experimental works by other research groups demonstrate that such Azo stars assemble into needle-like structures with light-responsive properties. Disregarding the response to light, we intend to characterize the equilibrium state of this system on the molecular scale. In particular, we aim to develop a thorough understanding of the binding mechanism between the molecules and analyze the structural properties of columnar stacks of Azo stars. Our study employs fully atomistic molecular dynamics (MD) simulations to model pre-assembled aggregates with various sizes and arrangements in water. In our detailed approach, we decompose the binding energies of the aggregates into the contributions due to the different types of non-covalent interactions and the contributions of the functional groups in the Azo stars. Initially, we investigate the origin and strength of the non-covalent interactions within a stacked dimer. Based on these findings, three arrangements of longer columnar stacks are prepared and equilibrated. We confirm that the binding energies of the stacks are mainly composed of π–π interactions between the conjugated parts of the molecules and hydrogen bonds formed between the stacked BTA cores. Our study quantifies the strength of these interactions and shows that the π–π interactions, especially between the Azo moieties, dominate the binding energies. We clarify that hydrogen bonds, which are predominant in BTA stacks, have only secondary energetic contributions in stacks of Azo stars but remain necessary stabilizers. Both types of interactions, π–π stacking and H-bonds, are required to maintain the columnar arrangement of the aggregates.     

Interligand interactions involved in the molecular recognition between copper(II) complexes and adenine or related purines

The available crystal structure information in the CSD database on ternary species prepared by the reaction of diverse copper(II) complexes (CuL) and purine, adenine and guanine or related purine derivatives is considered in order to deepen the intra-molecular interligand interactions affecting the molecular recognition patterns of the ‘metal complex + purine nucleobase’ and closely related systems. The degree of protonation and the possibilities of different tautomeric forms in the purine-like moieties are taken into account. The main conclusion is a general trend to form a CuN(purine-like) coordination bond which can be reinforced by an intra-molecular interligand H-bonding interaction. NH(purines)A (O or Cl acceptor) or NH(amino ligand L)O6(oxo-purines) are commonly observed. In addition, selected examples revealed that the presence of a variety of non-coordinating groups in L or in the purine-like nucleobases can significantly influence the structurally observed molecular recognition pattern. Moreover, examples are known where binuclear cores of the types Cu^II₂(μ₂-N3,N9-adeninate)₄(aqua)₂ or Cu^I₂(μ₂-N3,N9-adeninate)₂(aqua)₂ recognise CuL chelates by means of the expectable pattern (CuN7 coordination bond + N6HO(L) interaction).     

The 3,5-dimethyl-4-nitropyrazole ligand in the construction of supramolecular networks of silver(I) complexes

Three new ionic silver complexes based on the 3,5-dimethyl-4-nitropyrazole ligand (Hpz^NO₂) and 1:2 or 1:3 (Ag:Hpz^NO₂) stoichiometries, [Ag(Hpz^NO₂)₂][BF₄], [Ag(Hpz^NO₂)₃][SbF₆] and [Ag(Hpz^NO₂)₃][PO₂F₂]·Hpz^NO₂ have been prepared and structurally characterised. The linear or trigonal metallic coordination environment, the NO₂ groups on the pyrazole ligand as well as the presence of counteranions of the type as , or (the latter one evolving to ) were strategically selected to produce molecular assemblies established on the basis of hydrogen-bonds (N-H?X) and π?π or coordinative interactions involving the NO₂ group. The complex [Ag(Hpz^NO₂)₂][BF₄] exhibited polymeric N-H?F hydrogen-bonded chains which were assembled in a 3D network by weaker coordinative Ag?O(NO₂) and π(NO₂)?π(NO₂) interactions. In the complex [Ag(Hpz^NO₂)₃][SbF₆], consistent with the three-coordinated molecular environment, the interactions were extended to give rise an open 3D cationic sub-network in which the counteranions were encapsulated. By contrast, in the related complex [Ag(Hpz^NO₂)₃][PO₂F₂]·Hpz^NO₂ the presence of a fourth non-coordinated pyrazole Hpz^NO₂ avoided the formation of a 3D network giving rise to a double-chained 1D structure.     

Synthesis, crystal structure, and magnetic properties of two 3d-4f heterometallic coordination polymers

Two new 4f-3d heterometallic coordination polymers, [Gd₂^IIICo^II(pydc)₃(ox)(H₂O)₄)·2H₂O] (1) and [Dy^IIICu^II(pydc)₂(ox)_1/2(H₂O)₂·H₂O] (2) (pydc = pyridine-2,5-dicarboxylate anion, ox = oxalate dianion) were successfully synthesized under hydrothermal condition. Structure and magnetism of the two coordination polymers were characterized by single crystal X-ray diffraction and Quantum Design (MPMS) SQUID magnetometer. In both compounds, metal centers were connected by double ligand bridges. In 1 the gadolinium ions were linked in sheets by OCO ligand bridges and these sheets were connected by separated cobalt coordination spheres to generate the overall 2-D structure. In 2 the dysprosium centers were constructed into one dimensional chain by OCO bridges from pydc ligand bridges and these chains were linked by oxalate bridges to form sheets and different sheets were connected by copper coordination planes. The copper centers in 2 were linked in chain by elongated OCO brides and the chains were connected by hydrogen bond to generate 3-D structure. Magnetic properties of the two complexes were investigated by variable temperature magnetic susceptibility. The magnetic data suggest that overall antiferromagnetic interactions are present in the two compounds.     

Crystallochemical Analysis of Rare-Earth Halogen-Containing π-Complexes

Ninety-six halogen-containing -complexes of rare-earth elements were studied to reveal how the volume of the area of action of the Ln atom in coordination polyhedra LnC _n X _m (X = F, Cl, Br) depends on its nature, coordination and oxidation numbers, and on the number of Ln–X bonds. A method was proposed for estimating the ligand sizes in the coordination sphere by making use of the molecular Voronoi–Dirichlet polyhedra. The effect of the ligand sizes on the stability of -complexes and formation of aghostic contacts in their structures was analyzed.     

Yada: a novel tool for molecular docking calculations

Molecular docking is a computational method employed to estimate the binding between a small ligand (the drug candidate) and a protein receptor that has become a standard part of workflow in drug discovery. Generally, when the binding site is known and a molecule is similar to known ligands, the most popular docking methods are rather accurate in the prediction of the geometry. Unfortunately, when the binding site is unknown, the blind docking analysis requires large computational resources and the results are often not accurate. Here we present Yada, a new tool for molecular docking that is capable to distribute efficiently calculations onto general purposes computer grid and that combines biological and structural information of the receptor. Yada is available for Windows and Linux and it is free to download at www.yada.unisa.it.     

Molecular complexes of octafluoronaphthalene with catenated chalcogen-nitrogen compounds C6H5-X-NSN-SiMe3 (X = S, Se)

Mismatched molecular 1:1 complexes of C₁₀F₈ with catenated chalcogen-nitrogen compounds C₆H₅-X-NSN-SiMe₃ (X = S, Se) were prepared and characterized by X-ray crystallography. The complexes provide examples of structurally non-rigid polyheteroatom molecules involved in non-covalent arene-polyfluoroarene π-stacking interactions. In going from homocrystals to the co-crystals, the molecular Z, E configuration of the catenated compounds changes from noticeably non-planar to perfectly planar, i.e. C₁₀F₈ acts as “molecular iron”. On the other hand, C₁₀H₈ does not produce complexes with C₆F₅-X-NSN-SiMe₃ (X = S, Se).     

Fimbrolide disulfanes: synthesis and crystal interactions

A series of novel fimbrolide disulfanes is synthesized and a crystal structure analysis reveals interesting inter-molecular halogen-bonding and CO?CO (carbonyl-carbonyl) dipolar interactions. Molecular modelling studies with the target protein display significant halogen-bonding interactions in the ligand -binding site.     

Competing ligand exchange-solid phase extraction method for the determination of the complexation of dissolved inorganic mercury (II) in natural waters

A method employing dual competitive ligand exchange followed by solid phase extraction (CLE-SPE) for characterizing the complexation of inorganic Hg(II) in natural waters is described. This method employs parallel use of two competing ligands: diethyldithiolcarbamate (DEDC), which forms hydrophobic complexes with Hg(II), and thiosalicylic acid (TSA), which forms hydrophilic complexes with Hg(II). Inorganic mercury complexed by natural and competing ligands are separated based on hydrophobicity using C₁₈ solid phase extraction columns.Data modeling allows for the calculation of the concentration and conditional stability constants of natural ligands capable of complexing Hg(II) in both the operationally defined hydrophilic and hydrophobic fractions. The use of multiple ligand concentrations, and thus multiple analytical windows, to characterize different ligand classes within both of these two fractions is described. Studies of the kinetics of the ligand exchange involved, potential for changes in the stability of natural ligands during freezing and thawing, potential breakthrough during solid phase extraction, as well as the method's precision and estimation of error, are presented and discussed.Results from the application of the method to natural freshwaters demonstrated that in the limited samples collected over 99.99% of the ambient inorganic mercury is strongly complexed by ligands with conditional stability constants (, Hg²⁺) on the order of 10³⁰, values similar to that of reduced sulfur ligands. At ambient conditions 85-90% of the mercury exists in hydrophobic complexes in these freshwaters, but strong Hg-binding ligands exist in both the hydrophobic and hydrophilic fractions.     

Dihydrogen, dihydride and in between: NMR and structural properties of iron group complexes

Tabulating the structures and characteristic NMR properties of 17 iron complexes, 98 ruthenium complexes and 70 osmium complexes that contain dihydrogen or compressed dihydride ligands reveals a variety of trends. The HH bond lengths increase from similar Fe(II) to Ru(II) to Os(II) complexes. Iron(II) displays a narrow range of HH distances for stable complexes. Electronegative atoms Cl and O, when attached on the metal trans to the dihydrogen ligand, result in elongation of the HH bond relative to more electropositive atoms H, C, P and N. The family of cyclopentadienyl ligands also causes this elongating effect. The dihydrogen ligands with short HH distances and weak interactions with the metal, especially on iron and ruthenium are in the fast spinning regime. One exception is the biporphyrin complex of ruthenium with the side-on bridging H₂ ligand which has an HH distance of 118 pm but is in the fast spinning regime. There are some ruthenium complexes with HH distances greater than 110 pm that are in the slow motion regime and several complexes of osmium with HH distances greater than 130 pm that are in this regime. The large J_HH due to quantum mechanical exchange coupling are observable for some of these osmium complexes with HH distances in the range of 140–160 pm. The dihydrogen ligands in many complexes appear to have librational motions or other motions that place them in the intermediate motion regime. New equations to correlate J_HD with HH distances for ruthenium dihydrogen complexes and for osmium dihydrogen complexes are introduced here.     

D3R Grand Challenge 2: blind prediction of protein–ligand poses,affinity rankings,and relative binding free energies

The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 subchallenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 subchallenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarizes all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank (http://www.pdb.org), and in affinity ranking and scoring of bound ligands.     

2D and 3D supramolecular assemblies of double cyclopalladated azobenzenes realized by C-H?Cl-Pd, π?π and C-H?π interactions

The double cyclopalladated complex with azobenzene, μ-[(E)-1,2-diphenyldiazene-C^2,8, N^1,2]-di-[chloro(dimethylsulfoxide)palladium(II)]; (DMSO)PdCl(μ-C₆H₄NNC₆H₄)(DMSO)PdCl (1) and its analogous complex with DMF as ancillary ligand, (DMF)PdCl(μ-C₆H₄NNC₆H₄)(DMF)PdCl; μ-[(E)-1,2-diphenyldiazene-C^2,8,N^1,2]-di-[chloro(dimethylformamide)palladium(II)] (2a) were synthesized and the function of cyclopalladated moiety in molecular assembling in the solid state is illustrated by their crystal packings. The polymorphism of 2a and 2b is discussed. The crystal structures reveal assemblies with molecular components self-organized by C-H?Cl-Pd hydrogen bonds, π?π, and C-H?π interactions. The double cyclopalladated complexes of azobenzene, with two Pd-Cl moieties participating in the hydrogen bond formation and π-conjugated system involved in the π?π or C-H?π interactions, represent a new class of building blocks for construction of solid state supramolecular assemblies.