Detection of low-abundance protein phosphorylation by selective 18O labeling and mass spectrometry.

Reversible phosphorylation regulates the majority of intracellular networking and pathways. The study of this widely explored post-translational modification is usually challenged by low stoichiometric levels of modification. Many approaches have been developed to overcome this problem and to achieve rigorous characterization of protein phosphorylation.

Identification of fibrocytes from mesenchymal stem cells in keloid tissue: a potential source of abnormal fibroblasts in keloid scarring.

Abnormal fibroblasts have been implicated in keloid formation, a benign but fibroproliferative skin disorder. However, the exact source of these cells remains unknown. Fibrocytes are considered to be hybrid mesenchymal/hematopoietic cells, having been identified in various fibrotic disorders as the precursors of fibroblasts.

Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope.

A high-throughput screening protocol for evaluating chimeric, self-sufficient P450 biocatalysts and their mutants against a panel of substrates was developed, leading to the identification of a number of novel biooxidation activities.

Mixed SAMs and MALDI-ToF MS: preparation of N-glycosylamine derivative and thioctic acid methyl ester bearing 1,2-dithiolane groups and detection of enzymatic reaction on Au.

Herein, we report an enzymatic galactosylation reaction of β-glucopyranosylamide 4 and thioctic acid methyl ester 5 bearing 1,2-dithiolane groups to form a new system of mixed self-assembled monolayers (SAMs) on gold. Characterization of the enzymatic activity was conveniently achieved by mass spectrometry.

Comparative genomic hybridisation analysis of keloid tissue in Caucasians suggests possible involvement of HLA-DRB5 in disease pathogenesis.

Keloid disease (KD) is a common fibroproliferative disorder that can occur following cutaneous injury in genetically susceptible individuals. Familial predisposition, high prevalence in certain populations and occurrence in twins suggest a strong genetic component to KD. However, to date no single causative gene has been identified.

Addition of novel degenerate electrical waveform stimulation with photodynamic therapy significantly enhances its cytotoxic effect in keloid fibroblasts: first report of a potential combination therapy.

Background: We recently reported use of photodynamic therapy (PDT) for treating keloid disease (KD). However, in view of high recurrence rates post any treatment modality, adjuvant therapies should be considered. Additionally, we previously demonstrated the effect of a novel electrical waveform, the degenerate wave (DW) on differential gene expression in keloid fibroblasts.

Fully analytical integration over the 3D volume bounded by the β sphere in topological atoms.

Atomic properties of a topological atom are obtained by 3D integration over the volume of its atomic basin. Algorithms that compute atomic properties typically integrate over two subspaces: the volume bounded by the so-called β sphere, which is centered at the nucleus and completely contained within the atomic basin, and the volume of the remaining part of the basin. Here we show how the usual quadrature over the β sphere volume can be replaced by a fully analytical 3D integration leading to the atomic charge (monopole moment) for s, p, and d functions.

Nature of Chemical Interactions from the Profiles of Electron Delocalization Indices.

We analyze the behavior of the profiles of delocalization indices (DIs) between relevant pairs of atoms along reaction coordinates for a set of model chemical processes. A relationship between the topology of the DI and the nature of the underlying chemical change is reported. As shown, exponential shapes correspond to the traditional category of repulsive/nonbonded interactions, while sigmoidal profiles signal the formation/breaking of chemical links.

pKa prediction from an ab initio bond length: part 3--benzoic acids and anilines.

The prediction of pK(a) from a single ab initio bond length has been extended to provide equations for benzoic acids and anilines. The HF/6-31G(d) level of theory is used for all geometry optimisations. Similarly to phenols (Part 2 of this series of publications), the meta-/para-substituted benzoic acids can be predicted from a single model constructed from one bond length.

pKa prediction from an ab initio bond length: part 2--phenols.

The prediction of pK(a) continues to attract much attention with ongoing investigations into new ways to predict pK(a) accurately, where predicted pK(a) values deviate less than 0.50 log units from experiment. We show that a single descriptor, i.

Palladium(II)-mediated assembly of biotinylated ion channels.

Simple synthetic methodology has been used to create biotinylated pyridyl cholate lipids that can undergo multiple self-assembly events when inserted into phospholipid vesicles; Pd(II) links cholates into transmembrane lipids, while avidin laterally clusters these complexes together and concomitantly assembles the vesicles into aggregates. The transmembrane assembly of cholates by Pd(II) "opened" the ion channels, whereas avidin addition produced vesicle aggregates, giving a system that mimicked both transmembrane transport and cellular adhesion. Complexation of these Pd(II)-linked cholates by avidin gave a measurable decrease in ion flow, suggesting some channels became blocked or were prevented from adopting the optimum geometry for ion conduction.

Recent applications of ring-closing metathesis in the synthesis of lactams and macrolactams.

Lactams are an important class of compounds owing to their presence in numerous biologically active molecules of natural and unnatural nature. They are also highly versatile intermediates that can be elaborated into interesting compounds for potential use in organic and medicinal chemistry endeavors. In this feature article, the reader will be given a background to olefin metathesis followed by concise discussions (with selected examples) to report recent applications of ring-closing metathesis to form lactams and macrolactams from acyclic diene precursors, an area which continues to deposit attractive applications in the chemical literature en route or in the final step to the target molecules.

Simulation of liquid imidazole using a high-rank quantum topological electrostatic potential.

Rigid body molecular dynamics simulations were carried out on pure liquid imidazole at four different temperatures and at 1 atm. Imidazole, which is important both in life science and materials science, is one of the simplest molecules to possess both a lone pair and a π system. These two features are known to benefit from multipolar electrostatics.

Properties of liquid water from a systematic refinement of a high-rank multipolar electrostatic potential.

We build on previous work [S. Y. Liem and P.

A convenient approach to acyclic unsaturated amino acids via ring-closing metathesis.

An efficient synthetic methodology to gain access to novel cis- and trans-unsaturated amino acids via ring-closing metathesis in high yields is described.

In silico techniques for the identification of bioisosteric replacements for drug design.

This article provides an overview of the broad and increasingly varied selection of computational approaches available to find bioisosteric replacements for fragments of bioactive compounds. The rapidly increasing number and diversity of methods has provided medicinal chemists with a powerful range of commercial and academic tools to aid in the optimization of lead compound activity and ADMET properties for drug design. We discuss methods with fundamentally different philosophies, ranging from evaluation of similarity in a calculated property space to cheminformatics analysis of pharmaceutical compound databases.

Genetics of keloid scarring.

Keloid scarring, also known as keloid disease (KD), is a common, abnormally raised fibroproliferative cutaneous lesion that can occur following even minor skin trauma. The aetiopathogenesis of KD has remained an enigma todate compounded by an ill-defined clinical management. There is strong evidence suggesting a genetic susceptibility in individuals affected by KD, including familial heritability, common occurrence in twins and high prevalence in certain ethnic populations.

Prediction of the basicities of pyridines in the gas phase and in aqueous solution.

The basicities of 125 pyridine derivatives in the gas phase and in water have been correlated with the electron density properties within the framework of quantum topological molecular similarity (QTMS). We used the theory of quantum chemical topology (QCT) to provide ab initio descriptors that are able to predict pK(b) values. Partial least squares (PLS) and the machine-learning technique Kriging generated validated models.

pK(a) prediction from "Quantum Chemical Topology" descriptors.

Knowing the pK(a) of a compound gives insight into many properties relevant to many industries, in particular the pharmaceutical industry during drug development processes. In light of this, we have used the theory of Quantum Chemical Topology (QCT), to provide ab initio descriptors that are able to accurately predict pK(a) values for 228 carboxylic acids. This Quantum Topological Molecular Similarity (QTMS) study involved the comparison of 5 increasingly more expensive levels of theory to conclude that HF/6-31G(d) and B3LYP/6-311+G(2d,p) provided an accurate representation of the compounds studies.

Dynamically Polarizable Water Potential Based on Multipole Moments Trained by Machine Learning.

It is widely accepted that correctly accounting for polarization within simulations involving water is critical if the structural, dynamic, and thermodynamic properties of such systems are to be accurately reproduced. We propose a novel potential for the water dimer, trimer, tetramer, pentamer, and hexamer that includes polarization explicitly, for use in molecular dynamics simulations. Using thousands of dimer, trimer, tetramer, pentamer, and hexamer clusters sampled from a molecular dynamics simulation lacking polarization, we train (artificial) neural networks (NNs) to predict the atomic multipole moments of a central water molecule.

Quantum Isostere Database: a web-based tool using quantum chemical topology to predict bioisosteric replacements for drug design.

This paper introduces the 'Quantum Isostere Database' (QID), a Web-based tool designed to find bioisosteric fragment replacements for lead optimization using stored ab initio data. A wide range of original geometric, electronic, and calculated physical properties are stored for each fragment. Physical descriptors with clear meaning are chosen, such as distribution of electrostatic potential energy values across a fragment surface and geometric parameters to describe fragment conformation and shape from ab initio structures.

Prediction of interaction energies of substituted hydrogen-bonded Watson-Crick cytosine:guanine(8X) base pairs.

We investigated the variation in the interaction energy between the Watson-Crick hydrogen-bonded DNA base pairs guanine and cytosine (G(8X):C), where guanine is substituted in the C8 position by 37 different functional groups. Base pairs were optimized at the B3LYP/6-311+G(2d,p) level. A base pair complex containing a more strongly electron-withdrawing group remarkably forms a more stable base pair with C.

A refined model for prediction of hydrogen bond acidity and basicity parameters from quantum chemical molecular descriptors.

Abraham's H-bonding parameters alpha and beta have been described in terms of a minimal set of readily obtainable molecular descriptors. These parameters are basically equilibrium constants for complexation of acids with a reference base (alpha) or bases with a reference acid (beta) measured in a non-hydrogen bonding solvent such as tetrachloromethane. The models were developed using partial least squares with a diverse dataset recently compiled by Platts et al.

Design, synthesis and assaying of potential aquaporin inhibitors.

The aquaporin protein family performs fundamental tasks in the physiology of several organs in the human body. Their roles in several disorders known to involve water movement make them attractive targets for the development of novel drug therapies.This chapter describes assays commonly used to study the water permeability across AQPs.

Beyond Point Charges: Dynamic Polarization from Neural Net Predicted Multipole Moments.

Intramolecular polarization is the change to the electron density of a given atom upon variation in the positions of the neighboring atoms. We express the electron density in terms of multipole moments. Using glycine and N-methylacetamide (NMA) as pilot systems, we show that neural networks can capture the change in electron density due to polarization.