Accelerated Recursive Feature Elimination Based on Support Vector Machine for Key Variable Identification

Key variable identification for classifications is related to many trouble-shooting problems in process industries. Recursive feature elimination based on support vector machine （SVM-RFE） has been proposed recently in application for feature selection in cancer diagnosis. In this paper, SVM-RFE is used to the key variable selection in fault diagnosis, and an accelerated SVM-RFE procedure based on heuristic criterion is proposed. The data from Tennessee Eastman process （TEP） simulator is used to evaluate the effectiveness of the key variable selection using accelerated SVM-RFE （A-SVM-RFE）. A-SVM-RFE integrates computational rate and algorithm effectiveness into a consistent framework. It not only can correctly identify the key variables, but also has very good computational rate. In comparison with contribution charts combined with principal component aralysis （PCA） and other two SVM-RFE algorithms, A-SVM-RFE performs better. It is more fitting for industrial application.     

The Application of an Emerging Technique for Protein–Protein Interaction Interface Mapping: The Combination of Photo-Initiated Cross-Linking Protein Nanoprobes with Mass Spectrometry

Protein–protein interaction was investigated using a protein nanoprobe capable of photo-initiated cross-linking in combination with high-resolution and tandem mass spectrometry. This emerging experimental approach introduces photo-analogs of amino acids within a protein sequence during its recombinant expression, preserves native protein structure and is suitable for mapping the contact between two proteins. The contact surface regions involved in the well-characterized interaction between two molecules of human 14-3-3ζ regulatory protein were used as a model. The employed photo-initiated cross-linking techniques extend the number of residues shown to be within interaction distance in the contact surface of the 14-3-3ζ dimer (Gln8–Met78). The results of this study are in agreement with our previously published data from molecular dynamic calculations based on high-resolution chemical cross-linking data and Hydrogen/Deuterium exchange mass spectrometry. The observed contact is also in accord with the 14-3-3ζ X-ray crystal structure (PDB 3dhr). The results of the present work are relevant to the structural biology of transient interaction in the 14-3-3ζ protein, and demonstrate the ability of the chosen methodology (the combination of photo-initiated cross-linking protein nanoprobes and mass spectrometry analysis) to map the protein-protein interface or regions with a flexible structure.     

Prediction of solid–gas equilibria with the Peng–Robinson equation of state

In many applications related to Supercritical-Fluid (SCF) technology, solids are dissolved in SC fluids. Experimental data are now available for many systems but cannot cover all cases of potential practical interest. The prediction of solid solubilities in SC fluids, often in the presence of co-solvents, is useful for rational design of SCF extraction and related processes. Recently, thermodynamics has made considerable steps towards describing complex systems (gases with polar compounds) at high pressures using the so-called Equation of State/Excess Gibbs Free Energy (EoS/G^E) models. The success of these models is so far restricted to Vapor–Liquid Equilibria (VLE) for which they have been primarily developed and tested. In this work we evaluate such a predictive model, the LCVM EoS, for solid–gas equilibria (SGE) including systems with co-solvents. LCVM is chosen due to its success for VLE of asymmetric systems such as CO₂ with heavy alkanes and alcohols. Successful predictions are obtained for several solids as well as for some systems with co-solvents, but the results are less satisfactory for complex, multifunctional solids. A discussion of several factors, which affect modeling of SGE with cubic EoS, is included.     

Virtual Pharmacophore Screening Identifies Small-Molecule Inhibitors of the Rev1-CT/RIR Protein–Protein Interaction

Translesion synthesis (TLS) has emerged as a mechanism through which several forms of cancer develop acquired resistance to first-line genotoxic chemotherapies by allowing replication to continue in the presence of damaged DNA. Small molecules that inhibit TLS hold promise as a novel class of anticancer agents that can serve to enhance the efficacy of these front-line therapies. We previously used a structure-based rational design approach to identify the phenazopyridine scaffold as an inhibitor of TLS that functions by disrupting the protein–protein interaction (PPI) between the C-terminal domain of the TLS DNA polymerase Rev1 (Rev1-CT) and the Rev1 interacting regions (RIR) of other TLS DNA polymerases. To continue the identification of small molecules that disrupt the Rev1-CT/RIR PPI, we generated a pharmacophore model based on the phenazopyridine scaffold and used it in a structure-based virtual screen. In vitro analysis of promising hits identified several new chemotypes with the ability to disrupt this key TLS PPI. In addition, several of these compounds were found to enhance the efficacy of cisplatin in cultured cells, highlighting their anti-TLS potential.     

Terminal Protection of Small Molecule-Linked DNA for Small Molecule–Protein Interaction Assays

Methods for the detection of specific interactions between diverse proteins and various small-molecule ligands are of significant importance in understanding the mechanisms of many critical physiological processes of organisms. The techniques also represent a major avenue to drug screening, molecular diagnostics, and public safety monitoring. Terminal protection assay of small molecule-linked DNA is a demonstrated novel methodology which has exhibited great potential for the development of simple, sensitive, specific and high-throughput methods for the detection of small molecule–protein interactions. Herein, we review the basic principle of terminal protection assay, the development of associated methods, and the signal amplification strategies adopted for performance improving in small molecule–protein interaction assay.     

Multivalent Ligands with Tailor-Made Anion Binding Motif as Stabilizers of Protein–Protein Interactions

Modulation of protein–protein interactions (PPIs) is essential for understanding and tuning biologically relevant processes. Although inhibitors for PPIs are widely used, the field still lacks the targeted design of stabilizers. Here, we report unnatural stabilizers based on the combination of multivalency effects and the artificial building block guanidiniocarbonylpyrrol (GCP), an arginine mimetic. Unlike other GCP-based ligands that modulate PPIs in different protein targets, only a tetrameric design shows potent activity as stabilizer of the 14-3-3ζ/C-Raf and 14-3-3ζ/Tau complexes in the low-micromolar range. This evidences the role of multivalency for achieving higher specificity in the modulation of PPIs.     

Modulating Protein–Protein Interactions with Visible-Light-Responsive Peptide Backbone Photoswitches

Life relies on a myriad of carefully orchestrated processes, in which proteins and their direct interplay ultimately determine cellular function and disease. Modulation of this complex crosstalk has recently attracted attention, even as a novel therapeutic strategy. Herein, we describe the synthesis and characterization of two visible-light-responsive peptide backbone photoswitches based on azobenzene derivatives, to exert optical control over protein–protein interactions (PPI). The novel peptidomimetics undergo fast and reversible isomerization with low photochemical fatigue under alternatively blue-/green-light irradiation cycles. Both bind in the nanomolar range to the protein of interest. Importantly, the best peptidomimetic displays a clear difference between isomers in its protein-binding capacity and, in turn, in its potential to inhibit enzymatic activity through PPI disruption. In addition, crystal structure determination, docking and molecular dynamics calculations allow a molecular interpretation and open up new avenues in the design and synthesis of future photoswitchable PPI modulators.     

Interaction of the chromium–iron black pigment with porcelanised stoneware

A study has been undertaken on the interaction between the (Fe,Cr)₂O₃ black pigment and an industrial porcelanised stoneware composition at its firing temperature. The results indicate that the glassy phase that forms during firing preferentially extracts Fe₂O₃ from the pigment and probably contributes some Al₂O₃ to it, enriching the pigment composition in Cr₂O₃, without changing pigment crystal structure. The pigment alteration process mainly affects porcelanised stoneware microstructure and, to a lesser extent, color.     

Interaction of carbon monoxide with Cu–Pd and Cu–Ni bimetallic clusters

Interaction of CO with Cu–Pd and Cu–Ni bimetallic clusters deposited on a ZnO substrate has been investigated by core-level spectroscopy. The surface reactivity of both these alloy clusters increases with the decrease in cluster size, giving rise to dissociative adsorption at small cluster size. The surface reactivity also increases with the increase in Pd or Ni content and the reactivity of the alloy clusters is unlike that of either component metal. Thus, dissociative adsorption occurs on small Cu–Pd clusters unlike on either Cu or Pd clusters of comparable size. The reactivity of the Cu–Ni clusters, on the other hand, falls somewhere between those of Cu and Ni clusters. This revised version was published online in August 2006 with corrections to the Cover Date.     

Study of Ribavirin–Nucleic Acids Interaction

The UV–Vis absorption spectra of ribavirin in the absence and presence of calf thymus DNA are presented and discussed in this paper. The molecular structure of ribavirin was investigated by the semiempirical AM1 method, which triggered two polymorphic modifications of the antiviral drug also reported in the literature. Our experimental results point out two types of the binding. The first type involves a non-electrostatic (internal) binding, consisting of the intercalation of drug between the nitrogenous bases of nucleic acid. The second type (an external binding) involves the drug binding to the nucleic acid grooves. In addition, the binding constant of the second process has an order of magnitude greater than the binding constant for the first process, calculated by the Benesi–Hildebrand, Scott, and Scatchard methods, which supposes a 1:1 binding ratio. Also, the interactions of two polymorphic modifications of ribavirin (V₁ and V₂) with nucleic acids by the molecular mechanic and semiempirical AM1 methods were analyzed. The experimental data pointed out that in the ribavirin–nucleic acid complexes, the 1,2,4-triazole-3-carboxamide chromophore is intercalated between the bases of the nucleic acid sequences, the carboxamidic group is set outside of the nucleic acid sequence toward the major groove, and the 2-hydroxymethyl-tetrahydrofuran-3,4-diol fragment is located in the minor groove. In order to stress the sequence specificity of ribavirin, different models of the nucleic acid sequences containing adenine (A), thymine (T), cytosine (C), and guanine (G) in AAAAAA, TTTTTT, CCCCCC, GGGGGG, ATATAT, CGCGCG, ATCGAT, and CGATCG were used. The theoretical results outline the differences in the contributions of the electrostatic and van der Waals interactions to the total binding energy and the preference of ribavirin for the binding at the sequences of nucleic acids containing adenine and thymine bases.     

Targeted Nanoswitchable Inhibitors of Protein–Protein Interactions Involved in Apoptosis

Progress in drug delivery is hampered by a lack of efficient strategies to target drugs with high specificity and precise spatiotemporal regulation. The remote control of nanoparticles and drugs with light allows regulation of their action site and dosage. Peptide-based drugs are highly specific, non-immunogenic, and can be designed to cross the plasma membrane. In order to combine target specificity and remote control of drug action, here we describe a versatile strategy based on a generalized template to design nanoswitchable peptides that modulate protein–protein interactions upon light activation. This approach is demonstrated to promote photomodulation of two important targets involved in apoptosis (the interactions Bcl-xL–Bak and MDM2–p53), but can be also applied to a large pool of therapeutically relevant protein–protein interactions mediated by α-helical motifs. The template can be adjusted using readily available information about hot spots (residues contributing most to the binding energy) at the protein–protein interface of interest.     

Protein Chemical Synthesis Combined with Mirror-Image Phage Display Yields d-Peptide EGF Ligands that Block the EGF–EGFR Interaction

The epidermal growth factor (EGF) pathway, being overactive in a number of cancers, is a good target for clinical therapy. Although several drugs targeting the EGF receptor (EGFR) are on the market, tumours acquire resistance very rapidly. As an alternative, small molecules and peptides targeting EGF have been developed, although with moderate success. Herein, we report the use of mirror-image phage display technology to discover protease-resistant peptides with the capacity to inhibit the EGF–EGFR interaction. After the chemical synthesis of the enantiomeric protein d -EGF, two phage-display peptide libraries were used to select binding sequences. The d versions of these peptides bound to natural EGF, as confirmed by surface acoustic waves (SAWs). High-field NMR spectroscopy showed that the best EGF binder, d -PI_4, interacts preferentially with an EGF region that partially overlaps with the receptor binding interface. Importantly, we also show that d -PI_4 efficiently disrupts the EGF–EGFR interaction. This methodology represents a straightforward approach to find new protease-resistant peptides with potential applications in cancer therapy.     

Three-Dimensional Structural Aspects of Protein–Polysaccharide Interactions

Linear polysaccharides are typically composed of repeating mono- or disaccharide units and are ubiquitous among living organisms. Polysaccharide diversity arises from chain-length variation, branching, and additional modifications. Structural diversity is associated with various physiological functions, which are often regulated by cognate polysaccharide-binding proteins. Proteins that interact with linear polysaccharides have been identified or developed, such as galectins and polysaccharide-specific antibodies, respectively. Currently, data is accumulating on the three-dimensional structure of polysaccharide-binding proteins. These proteins are classified into two types: exo-type and endo-type. The former group specifically interacts with the terminal units of polysaccharides, whereas the latter with internal units. In this review, we describe the structural aspects of exo-type and endo-type protein-polysaccharide interactions. Further, we discuss the structural basis for affinity and specificity enhancement in the face of inherently weak binding interactions.     

Interaction of molten aluminum with porous TiB2-based ceramics containing Ti–Fe additives

In this study, the wettability and interaction of porous TiB₂-based composites with liquid aluminum has been investigated. TiB₂ composites were consolidated with Ti and Fe additives using pressureless sintering. The composites show good wettability with respect to molten aluminum. During liquid infiltration, Ti and Fe additives are dissolved. Intermetallic compounds containing Ti, Fe and Al are formed within the penetration depth. Since these phases have melting points higher than the experiment's temperature (960 °C), isothermal solidification takes place during the penetration of molten aluminum. Liquid aluminum does not seem to attack the solid skeleton of the TiB₂ specimens and no signs of swelling or cracking were detected.     

Prediction of Cloud Point Curves of Alkyl Ethoxylates with the Hydrophilic–Lipophilic-Difference and Net-Average-Curvature (HLD-NAC) Framework

Understanding and predicting cloud point phenomena is important for the formulation of nonionic surfactant systems, and the design of cloud-phenomena-associated separation processes. There have been several approaches to fit and predict the cloud point phenomena, in most cases using bulk thermodynamic approaches. In this work, we introduced the hydrophilic–lipophilic-difference and net-average-curvature (HLD-NAC) as an interfacial (curvature) approach to predict cloud point values at different surfactant concentrations (cloud point curve). The HLD-NAC method could fully predict the cloud point of alkyl ethoxylate of pure surfactants, typically within 4 °C of the experimental values, using published HLD constants, and the molecular structure of the surfactants. For commercial (polydispersed) surfactants, the same level of accuracy can be achieved if the experimental cloud point at 1 wt.% is used to adjust the HLD values. One additional benefit of using the HLD framework is the ability to predict changes in the cloud point curve with the introduction of electrolytes. While other models can fit the experimental data within 1 °C, the greater uncertainty of the HLD-NAC (~4 °C) is a reasonable compromise given the simplicity of the approach.     

Chemical Space Overlap with Critical Protein–Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries

There is growing interest in the use of structure-based virtual screening to identify small molecules that inhibit challenging protein–protein interactions (PPIs). In this study, we investigated how effectively chemical library members docked at the PPI interface mimic the position of critical side-chain residues known as “hot spots”. Three compound collections were considered, a commercially available screening collection (ChemDiv), a collection of diversity-oriented synthesis (DOS) compounds that contains natural-product-like small molecules, and a library constructed using established reactions (the “screenable chemical universe based on intuitive data organization”, SCUBIDOO). Three different tight PPIs for which hot-spot residues have been identified were selected for analysis: uPAR⋅uPA, TEAD4⋅Yap1, and Ca_Vα⋅Ca_Vβ. Analysis of library physicochemical properties was followed by docking to the PPI receptors. A pharmacophore method was used to measure overlap between small-molecule substituents and hot-spot side chains. Fragment-like conformationally restricted small molecules showed better hot-spot overlap for interfaces with well-defined pockets such as uPAR⋅uPA, whereas better overlap was observed for more complex DOS compounds in interfaces lacking a well-defined binding site such as TEAD4⋅Yap1. Virtual screening of conformationally restricted compounds targeting uPAR⋅uPA and TEAD4⋅Yap1 followed by experimental validation reinforce these findings, as the best hits were fragment-like and had few rotatable bonds for the former, while no hits were identified for the latter. Overall, such studies provide a framework for understanding PPIs in the context of additional chemical matter and new PPI definitions.