A5010557335- Receptor Mechanisms and Signaling
- Metal-Catalyzed Oxygenation Mechanisms
- Biochemical Analysis and Sensing Techniques
- RNA and protein synthesis mechanisms
- Photoreceptor and optogenetics research
- Photochromic and Fluorescence Chemistry
- Ion channel regulation and function
- Olfactory and Sensory Function Studies
- Porphyrin Metabolism and Disorders
- Protein Structure and Dynamics
- Neuropeptides and Animal Physiology
- Enzyme-mediated dye degradation
- Free Radicals and Antioxidants
- Metal complexes synthesis and properties
- Glycosylation and Glycoproteins Research
- Advanced oxidation water treatment
- Cardiac electrophysiology and arrhythmias
- Influenza Virus Research Studies
- Bacterial Genetics and Biotechnology
- Carbohydrate Chemistry and Synthesis
- Liver Disease and Transplantation
- Heme Oxygenase-1 and Carbon Monoxide
- Machine Learning in Bioinformatics
- Lipid Membrane Structure and Behavior
- Monoclonal and Polyclonal Antibodies Research
Forschungszentrum Jülich
2017-2025
Heinrich Heine University Düsseldorf
2017-2025
Düsseldorf University Hospital
2021-2024
Universitat de Barcelona
2008-2023
Institute for Advanced Medical Research
2023
Temple University
2011-2016
University of Sassari
2014
Rutgers, The State University of New Jersey
2014
Rega Institute for Medical Research
2014
KU Leuven
2014
Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to water and oxygen (2H2O2 → 2 H2O + O2) with high efficiency. The enzyme is first oxidized a high-valent iron intermediate, known as Compound I (Cpd I) which, in contrast other hydroperoxidases, reduced back the resting state further reacting H2O2. By means of hybrid QM/MM Car−Parrinello metadynamics simulations, we have investigated mechanism reduction H2O2 Helicobacter pylori catalase (HPC)...
Significance The conduction of protons through the highly restricted paths transmembrane proteins is an essential process living systems and intriguing problem in modern physical chemistry. small size influenza M2 proton channel makes it ideal system for study transport across a membrane. Additionally, has medical relevance as anti-flu drug target. These high-resolution structures were obtained by crystallizing protein membrane-like environment reveal networks hydrogen-bonded waters that...
Horseradish peroxidase (HRP) is one of the most relevant enzymes, used extensively in immunochemistry and biocatalysis applications. Unlike closely related catalase it exhibits a low activity to disproportionate hydrogen peroxide (H2O2). The origin this disparity remains unknown due lack atomistic information on catalase-like reaction HRP. Using QM(DFT)/MM metadynamics simulations, we uncover mechanism for reduction HRP Compound I intermediate by H2O2 at atomic detail. begins with atom...
We demonstrate by QM/MM calculations that the formation of Compound 0, an intermediate in catalytic cycle horseradish peroxidase, is catalyzed a single water molecule, which relays proton transfer between substrate (H2O2) and acceptor (His42). Thus, molecule enhances thermodynamic kinetic acidities H2O2 many orders magnitude. The behavior during activation may account for experimental reports extensive entropic effects principal active species enzyme I.
We have investigated the dynamics of water molecules in distal pocket horseradish peroxidase to elucidate role that they may play formation principal active species enzymatic cycle (compound I, Por°+−FeIV═O) upon reaction resting FeIII state with hydrogen peroxide. The equilibrium molecular simulations show that, accord experimental evidence, site access channel is hydrated an average two three within 5 Å from bound Although always hydrated, specific conformations which a molecule bridges...
The role of amyloid β (Aβ) peptide in the onset and progression Alzheimer's disease is linked to presence soluble Aβ species. Sulfated glycosaminoglycans (GAGs) promote fibrillogenesis reduce toxicity neuronal cell cultures, but a satisfactory rationale explain these effects at molecular level has not been provided yet. We have used circular dichroism, Fourier transform infrared spectroscopy, fluorescence microscopy protease digestion, atomic force (AFM), dynamics simulations characterize...
Abstract Various single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene have been associated with behavioral traits, autism spectrum disorder (ASD) and other diseases. The non-synonymous SNP rs4686302 results OXTR variant A218T has linked to core characteristics of ASD, trait empathy preterm birth. However, molecular intracellular mechanisms underlying those associations are still elusive. Here, we uncovered consequences this mutation that may affect psychological or...
The 25 human bitter taste receptors (hTAS2Rs) are responsible for detecting molecules present in food, and they also play several physiological pathological roles extraoral compartments. Therefore, understanding their ligand specificity is important both food research pharmacological applications. Here we provide a molecular insight into the exquisite recognition of β-glycopyranosides by one members this receptor subclass, hTAS2R16. Most its agonists have common presence β-glycopyranose unit...
The structures of Helicobacter pylori (HPC) and Penicillium vitale (PVC) catalases, each with two subunits in the crystal asymmetric unit, oxidized peroxoacetic acid are reported at 1.8 1.7 Å resolution, respectively. Despite similar oxidation conditions employed, iron−oxygen coordination length is 1.72 for PVC, close to what expected a FeO double bond, 1.80 1.85 HPC, suggestive Fe−O single bond. structure electronic configuration oxoferryl heme immediate protein environment investigated...
Background and Purpose Anion‐selective Cys‐loop receptors (GABA glycine receptors) provide the main inhibitory drive in CNS. Both types of receptor operate via chloride‐selective ion channels, though with different kinetics, pharmacological profiles, localization. Disequilibrium their function leads to a variety disorders, which are often treated allosteric modulators. The few available GABA channel blockers effectively suppress currents neurons, but systemic administration is highly toxic....
Abstract Defective ion channel turnover and clearance of damaged proteins are associated with aging neurodegeneration. The L-type Ca V 1.2 voltage-gated calcium mediates depolarization-induced signals in heart brain. Here, we determined the interaction surface between actin two subunits, β 2 4 , using cross-linking mass spectrometry protein-protein docking, uncovered a role replenishing conduction-defective channels. Computational vitro mutagenesis identified hotspots that decreased affinity...
Catalase-peroxidases (KatGs) are bifunctional heme proteins, belonging to the family of class I peroxidases, that able catalyze both catalatic and peroxidatic reactions within a peroxidase-like structure. We investigated electronic structure reaction intermediates catalytic cycle KatGs by means density functional theory (DFT) QM/MM calculations. The outcome was ionization state KatG-specific covalent adduct (Met264-Tyr238-Trp111) affects radical character compound (Cpd I). Specifically, in...
Quantum chemical computations are used to study the electronic and structural properties of cob(I)alamin intermediate cobalamin-dependent methionine synthase (MetH). QM(DFT)/MM calculations on methylcobalamin (MeCbl) binding domain MetH reveal that transfer methyl group substrate is associated with displacement histidine axial base (His759). The oscillates between a His-on form in Me-cob(III)lamin:MetH resting state, where Co−N(His759) distance 2.27 Å, His-off cob(I)alamin:MetH (2.78 Å)....
The influenza virus PA endonuclease, which cleaves capped cellular pre-mRNAs to prime viral mRNA synthesis, is a promising target for novel anti–influenza therapeutics. catalytic center of this enzyme resides in the N-terminal part (PA-Nter) and contains two (or possibly one or three) Mg<sup>2+</sup> Mn<sup>2+</sup> ions, are critical its function. There great interest inhibitors that optimally designed occupy active site chelate metal ions. We focused here on series <i>β</i>-diketo acid...
Human G-protein coupled receptors (hGPCRs) constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste olfaction, along with variety other physiological processes. Hence these promising targets for pharmaceutical intervention. Molecular modeling has been so far most important tool to get insights on agonist binding activation. Here we investigate both aspects by...
Development of liver fibrosis is paralleled by contraction hepatic stellate cells (HSCs), the main profibrotic cells. Yet, little known about interplay neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer contraction, in fibrosis. We demonstrate that HSCs are source NEP. Importantly, NPY originates majorly from splanchnic region cleaved NEP order to terminate contraction. Interestingly, deficiency (Nep-/-) showed less but portal hypertension upon injury two different...
The key step in the catalytic cycle of methionine synthase (MetH) is transfer a methyl group from methylcobalamin (MeCbl) cofactor to homocysteine (Hcy). This mechanism has been traditionally viewed as an SN2-type reaction, but different based on one-electron reduction (reductive cleavage) recently proposed. In this work, we analyze whether plausible theoretical point view. By means combination gas-phase well hybrid QM/MM calculations, show that cleavage Co−C bond MeCbl···Hcy complex (Hcy =...
Heme catalases prevent cells from oxidative damage by decomposing hydrogen peroxide into water and molecular oxygen. Here we investigate the factors that give rise to an undesirable side reaction competing with normal catalase activity, migration of a radical heme active site protein in principal intermediate compound I (Cpd I). Recently, it has been proposed this electron transfer takes place Cpd Helicobacter pylori (HPC), but not Penicillium vitale (PVC), where oxidation equivalent remains...
Abstract The enzymatic hydrolysis of chitin, one the most abundant carbohydrates in nature, is achieved by chitinases, enzymes increasing importance biomedicine and industry. Unlike retaining glycosidases, family GH18 chitinases follow a substrate‐assisted mechanism which 2‐acetamido group N ‐acetylglucosamine monomer, rather than basic residue enzyme, reacts with sugar anomeric carbon, forming an intermediate that has been described as oxazolinium ion. Based on QM/MM metadynamics...
Abstract Substrates associate and products dissociate from enzyme catalytic sites rapidly, which hampers investigations of their trajectories. The high-resolution structure the native Hordeum exo-hydrolase HvExoI isolated seedlings reveals that non-covalently trapped glucose forms a stable enzyme-product complex. Here, we report alkyl β- d -glucoside methyl 6-thio-β-gentiobioside substrate analogues perfused in crystalline bind across site after they displace glucose, while...