A5022396850- interferon and immune responses
- Protein Structure and Dynamics
- Metal complexes synthesis and properties
- Viral Infections and Vectors
- Immune Response and Inflammation
- Cytokine Signaling Pathways and Interactions
- Chemical and Physical Properties in Aqueous Solutions
- Electrochemical Analysis and Applications
- Computational Drug Discovery Methods
- DNA and Nucleic Acid Chemistry
- Crystallography and molecular interactions
- Chemical Synthesis and Analysis
- Advanced Chemical Physics Studies
- Radioactive element chemistry and processing
- RNA regulation and disease
- Free Radicals and Antioxidants
- Influenza Virus Research Studies
- Mass Spectrometry Techniques and Applications
- Molecular spectroscopy and chirality
- Viral Infections and Outbreaks Research
- Radiopharmaceutical Chemistry and Applications
- Virology and Viral Diseases
- Peptidase Inhibition and Analysis
- Cancer and biochemical research
- Metalloenzymes and iron-sulfur proteins
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
2013-2025
Czech Academy of Sciences
2015-2025
Gilead Sciences (Australia)
2015
A carefully selected set of acyclic and cyclic model peptides several other macrocycles, comprising 13 compounds in total, has been used to calibrate the accuracy DFT(-D3) method for conformational energies, employing BP86, PBE0, PBE, B3LYP, BLYP, TPSS, TPSSh, M06-2X, B97-D, OLYP, revPBE, M06-L, SCAN, revTPSS, BH-LYP, ωB97X-D3 functionals. Both high- low-energy conformers, 15 or 16 each compound adding 196 denoted as MPCONF196 data set, were included, reference values obtained by composite...
Cyclic dinucleotides are second messengers in the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, which plays an important role recognizing tumor cells and viral or bacterial infections. They bind to STING adaptor protein trigger expression cytokines via TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) inhibitor nuclear factor-κB (IκB) (IKK)/nuclear (NFκB) signaling cascades. In this work, we describe enzymatic preparation 2′–5′,3′–5′-cyclic...
The most important experimental quantity describing the thermodynamics of metal-ion binding with various (in)organic ligands, or biomolecules, is stability constant complex (β). In principle, it can be calculated as free-energy change associated complexation, i.e., its uptake from solution under standard conditions. Because this process interactions charged species, large values interaction and solvation energies are in general involved. Using thermodynamic cycle (in vacuo complexation...
Cyclic dinucleotides (CDNs) are second messengers that bind to the stimulator of interferon genes (STING) and trigger expression type I interferons proinflammatory cytokines. Here we evaluate activity 3′,3′-c-di(2′F,2′dAMP) its phosphorothioate analogues against five STING allelic forms in reporter-cell-based assays rationalize our findings with X-ray crystallography quantum mechanics/molecular mechanics calculations. We show presence fluorine 2′ position improves not only wild (WT) but also...
STING (stimulator of interferon genes) is a key regulator innate immunity that has recently been recognized as promising drug target. activated by cyclic dinucleotides (CDNs) which eventually leads to expression type I interferons and other cytokines. Factors underlying the affinity various CDN analogues are poorly understood. Herein, we correlate structural biology, isothermal calorimetry (ITC) computational modeling elucidate factors contributing binding six CDNs-three pairs natural (ribo)...
We designed zinc(II)‐binding peptide featuring the Cys2His2 zinc‐finger motif. Several tens of thousands (His/Cys)‑Xn‑(His/Cys) protein fragments (n = 2 to 20) were extracted from 3D structures deposited in Protein Data Bank. Based on geometrical constraints positioning two Cys (C) and His (H) side chains at vertices a tetrahedron, approximately 22 000 sequences (H/C)‑Xi‑(H/C)‑Xj‑(H/C)‑Xk‑(H/C) type, satisfying Nmetal‑binding H Nmetal‐binding C 2, processed. To prove viability computational...
To address fundamental questions in bioinorganic chemistry, such as metal ion selectivity, accurate computational protocols for both the gas-phase association of metal-ligand complexes and solvation/desolvation energies species involved are needed. In this work, we attempt to critically evaluate performance ab initio DFT electronic structure methods available recent solvation models calculations energetics associated with complexation. On example five model ([M(II)(CH(3)S)(H(2)O)](+),...
Cyclam derivatives bearing one geminal bis(phosphinic acid), -CH2PO2HCH2PO2H2 (H2L(1)), or phosphinic-phosphonic acid, -CH2PO2HCH2PO3H2 (H3L(2)), pendant arm were synthesized and studied as potential copper(II) chelators for nuclear medical applications. The ligands showed good selectivity over zinc(II) nickel(II) ions (log KCuL = 25.8 27.7 H2L(1) H3L(2), respectively). Kinetic study revealed an unusual three-step complex formation mechanism. initial equilibrium step leads to out-of-cage...
Quantum and molecular mechanics (QM/MM) QM-only (cluster model) modeling techniques represent the two workhorses in mechanistic understanding of enzyme catalysis. One stringent tests for QM/MM and/or QM approaches is to provide quantitative answers real-world biochemical questions, such as effect single-point mutations on kinetics. This translates into predicting relative activation energies 1–2 kcal·mol–1 accuracy; predictions can be used rational design novel variants with desired/improved...
STING protein (stimulator of interferon genes) plays an important role in the innate immune system. A number potent compounds regulating its activity have been reported, mostly derivatives cyclic dinucleotides (CDNs), natural agonists. Here, we aim to provide complementary information large-scale "ligand-profiling" studies by probing importance STING-CDN protein-ligand interactions on side. We examined detail six typical CDNs each complex with 13 rationally devised mutations STING: S162A,...
To find and calibrate a robust reliable computational protocol for mapping conformational space of medium-sized molecules, exhaustive sampling has been carried out series seven macrocyclic compounds varying ring size one acyclic analogue. While five them were taken from the MD/LLMOD/force field study by Shelley co-workers (Watts, K. S.; Dalal, P.; Tebben, A. J.; Cheney, D. L.; Shelley, J. C. Macrocycle Conformational Sampling with MacroModel. Chem. Inf. Model. 2014, 54, 2680−2696), three...
To gain more insight into the physicochemical aspects of a protein structure from first principles, conformational space all 8000 "capped" tripeptides (i.e., N-Ac-X1X2X3-NH-CH3, where Xi is one 20 natural amino acids) was investigated computationally. An enormous dataset (denoted P-CONF_1.6M and containing close to 1 600 000 conformers in total) has been obtained by employing composite protocol combining density functional theory, semiempirical quantum mechanics (SQM), state-of-the-art...
The 3'-5', 3'-5' cyclic dinucleotides (3'3'CDNs) are bacterial second messengers that can also bind to the stimulator of interferon genes (STING) adaptor protein in vertebrates and activate host innate immunity. Here, we profiled substrate specificity four dinucleotide synthases from Vibrio cholerae (DncV), Bacillus thuringiensis (btDisA), Escherichia coli (dgcZ), Thermotoga maritima (tDGC) using a library 33 nucleoside-5'-triphosphate analogues then employed these enzymes synthesize 24...
Factors determining metal-ion selectivity in peptidic sites were elucidated using the recently benchmarked DFT(BP86-D3//COSMO-RS) computational protocol.
Computational “error bars” for modelling cyclic dinucleotides – NMR experiment<italic>vs.</italic>quantum mechanics and molecular dynamics.
Abstract Cyclic dinucleotides (CDNs) are important second messengers in bacteria and eukaryotes. Detailed characterization of their physicochemical properties is a prerequisite for understanding biological functions. Herein, we examine acid–base electromigration selected CDNs employing capillary electrophoresis (CE), density functional theory (DFT), nuclear magnetic resonance (NMR) spectroscopy to provide benchmark p K values, as well unambiguously determine the protonation sites. Acidity...
Abstract STING (stimulator of interferon genes) is a key regulator innate immunity that has recently been recognized as promising drug target. activated by cyclic dinucleotides (CDNs) which eventually leads to expression type I interferons and other cytokines. Factors underlying the affinity various CDN analogues are poorly understood. Herein, we correlate structural biology, isothermal calorimetry (ITC) computational modeling elucidate factors contributing binding six CDNs—three pairs...
ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionCorrection to "Interaction of Metal Ions with Biomolecular Ligands: How Accurate Are Calculated Free Energies Associated Ion Complexation?"Ondrej Gutten, Ivana Beššeová, and Lubomír Rulíšek*Cite this: J. Phys. Chem. A 2012, 116, 32, 8407Publication Date (Web):August 8, 2012Publication History Published online8 August 2012Published inissue 16...