A5086398107- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Glycosylation and Glycoproteins Research
- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Supramolecular Self-Assembly in Materials
- Cancer, Hypoxia, and Metabolism
- DNA and Nucleic Acid Chemistry
- Biochemical and Molecular Research
- Protein Interaction Studies and Fluorescence Analysis
- Enzyme Structure and Function
- Multiple Myeloma Research and Treatments
- Chemical Synthesis and Analysis
- Free Radicals and Antioxidants
- Lipid Membrane Structure and Behavior
- Protein purification and stability
- Epigenetics and DNA Methylation
- Virus-based gene therapy research
- Molecular spectroscopy and chirality
- Pharmacological Receptor Mechanisms and Effects
- Acute Lymphoblastic Leukemia research
- Surfactants and Colloidal Systems
- ATP Synthase and ATPases Research
- Metal-Catalyzed Oxygenation Mechanisms
- Ubiquitin and proteasome pathways
Jagiellonian University
2003-2015
The Honourable Society of Lincoln's Inn
2006-2010
Cancer Research UK
2006-2010
Mount Vernon Hospital
2006
Italian Institute of Telemedicine
2003
Polish Academy of Sciences
2000-2001
Georgia State University
2000
l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There wide individual variation in pharmacokinetics, and little known about its metabolism. The mechanisms failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which produced constitutively by normal leukemic cells, degraded asparaginase Escherichia coli (ASNase)...
Abstract In previous CAPRI rounds (3–5) we showed that using MD‐generated ensembles, as inputs for a rigid‐body docking algorithm, increased our success rate, especially targets exhibiting substantial amounts of induced fit. recent (6–11), cross‐docking was followed by short MD‐based local refinement the subset solutions with lowest interaction energies after minimization. The above approach promising results target 20, where were able to recover 30% native contacts one submitted models....
The self-assembling tendency and protein complexation capability of dyes related to Congo red also some different structure were compared explain the mechanism binding reason for its specific affinity beta-structure. Complexation with proteins was measured directly expressed as number dye molecules bound heat-aggregated IgG two light chains structural stability. Binding rabbit antibodies indirectly enhancement effect on immune complex formation. Self-assembling tested using dynamic...
This study describes the calculation of microscopic dissociation and tautomerization constants fluorescein its derivatives, 2',7'-dichlorofluorescein (DCF) 2',7'-difluorofluorescein (DFF), in an aqueous environment. In vacuo free energies were obtained using complete basis set (CBS) DFT-based methods, while solvation calculated with CPCM implicit protocol UAHF, UAKS, Pauling radii sets. Our results indicate that different vacuum protocols give energy changes upon within 1 kcal/mol each other...
Abstract Molecular Dynamics (MD) simulations have been performed on a set of rigid‐body docking poses, carried out over 25 protein–protein complexes. The results show that fully flexible relaxation increases the fraction native contacts (NC) by up to 70% for certain poses. largest increase in NC is observed poses where anchor residues are able sample their bound conformation. For each MD simulation, structural snap‐shots were clustered and centre cluster used as MD‐relaxed pose. A comparison...
The ordered amyloid‐like organization of protein aggregates was obtained using for their formation the rigid fibrillar nanostructures Congo red as scaffolding. higher rigidity used dye nanoparticles resulted from stronger stacking molecules at low pH (near p K amino group) because decreased charge repulsion. polylysine, human globin, and immunoglobulin L chain were arranged in this way to form deposits amyloid properties. scaffolding introduced simply by mixing proteins a or preorganized...
Gaucher disease is caused by the defective activity of lysosomal hydrolase, glucosylceramidase. Although x-ray structure wild type glucosylceramidase has been resolved, little known about structural features any >200 mutations. Various treatments for are available, including enzyme replacement and chaperone therapies. The latter involves binding competitive inhibitors at active site to enable correct folding transport mutant lysosome. We now use molecular dynamics, a set analysis tools,...
Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient transport avoid intracellular accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a that plays central role in pH modulation. The discovery optimization of novel class MCT4 inhibitors (hit 9a), identified by cellular screening MDA-MB-231, described. Direct target interaction the optimized compound 18n with cytosolic domain was shown after solubilization GFP-tagged...
Among specific amyloid ligands, Congo red and its analogues are often considered potential therapeutic compounds. However, the results of studies so far have not been univocal because properties this dye, derived mostly from supramolecular nature, still poorly understood. The structure red, formed by π-π stacking dye molecules, is susceptible to influence electric field, which may significantly facilitate electron delocalization. Consequently, field generate altered physico-chemical dye....
Congo red dye as well other eagerly self-assembling organic molecules which form rod-like or ribbon-like supramolecular structures in water solutions, appears to represent a new class of protein ligands with possible wide-ranging medical applications. Such associate proteins integral clusters and preferentially penetrate into areas low molecular stability. Abnormal, partly unfolded are the main binding target for such ligands, while packed generally inaccessible. Of particular interest is...
Abstract Congo red, a dye of high self‐assembling tendency, has been found to form complexes with proteins by adhesion the ribbon‐like supramolecular ligand polypeptide chains β‐conformation. Complexation is allowed local or global protein instability, facilitating penetration locus its binding. At elevated temperatures, L chain λ myeloma origin was two distinct easily differentiated in electrophoresis as slow‐ and fast‐migrating fractions, bearing four‐ eight‐dye‐molecule ligands,...
An allosteric mechanism for the generation of long‐distance structural alterations in Fab fragments antibodies immune complexes has been postulated and tested theoretical experimental analysis. The flexing and/or torsion‐derived forces exerted on elbow region arms bivalent upon binding to antigen were assumed drive disruption hydrogen bonds which stabilize N‐ C‐terminal chain V‐domains. This allows an extra movement followed by a relaxation arm may generate effects if, particular, changes...
It was shown experimentally that binding of a micelle composed Congo red molecules to immunological complexes leads the enhanced stability latter, and simultaneously prevents complement molecule (C1q). The dye binds in cavity created by removal N-terminal polypeptide chain, as observed model system-immunoglobulin G (IgG) light chain dimer. Molecular Dynamics (MD) simulations three forms IgG dimer, with without dye, were performed investigate role fragment self-assembled ligand coupling...
Congo red and a group of structurally related dyes long used to stain amyloid proteins are known associate in water solutions. The self-association some belonging this appears particularly strong. In solutions their molecules arranged ribbon-like micellar forms with liquid crystalline properties. These compounds have recently been found form complexes native non-standard way. Gaps formed by the local distribution beta-sheets probably represent receptor sites for these dye ligands. They may...
Lipoxygenases (LOs), which are non-heme-iron-containing enzymes, play a vital role in plant and mammalian organisms. Their active sites have been probed by various spectroscopic techniques both resting (Fe2+) (Fe3+) forms. Several crystal structures reported for ferrous forms of LOs; nevertheless, many unresolved questions still remained. In particular, subtle differences the first coordination sphere iron center seem to be very important their catalytic activity thus any information about...
The role of the N-terminal polypeptide fragment immunoglobulin l-chain in V domain packing stability, and flexibility whole chain was approached by molecular dynamics simulation. observations were supported experimental analysis. appeared to be low-stability element domain. At moderately elevated temperature it may replaced at its locus Congo red then removed proteolysis. After removal adsorption (diethylamino)ethyl (DEAE) cellulose, stability complete L devoid compared. results indicated...
Abstract The present study tests performance of different solvation models applied to molecular dynamics simulation a large, dimeric protein molecule. Analytical Continuum Electrostatics (ACE) with two parameter sets, older V98 and new V01, Effective Energy Function (EEF) are employed in immunoglobulin G (IgG) light chain dimer variable domain IgG chain. Results compared explicit solvent distance dependent dielectric constant (DDE) calculations. overall analysis shows that the EEF method...
Abstract The dye Congo red and related self-assembling compounds were found to stabilize immune complexes by binding antibodies currently engaged in complexation antigen. In our simulations, it was shown that the site becomes accessible for supramolecular ligand is located V domain, normally occupied N-terminal polypeptide chain fragment. of disrupts β-structure increasing plasticity antigen-binding site. higher fluctuation CDR-bearing loops enhances antigen binding, allows even low-affinity...