Base cations
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The hepatitis delta virus (HDV) ribozyme is an RNA enzyme from the human pathogenic HDV. Cations play a crucial role in self-cleavage of the HDV ribozyme, by promoting both folding and chemistry. Experimental studies have revealed limited but intriguing details on the location and structural and catalytic functions of metal ions. Here, we analyze a total of approximately 200 ns of explicit-solvent molecular dynamics simulations to provide a complementary atomistic view of the binding of monovalent and divalent cations as well as water molecules to reaction precursor and product forms of the HDV ribozyme. Our simulations find that an Mg2+ cation binds stably, by both inner- and outer-sphere contacts, to the electronegative catalytic pocket of the reaction precursor, in a position to potentially support chemistry. In contrast, protonation of the catalytically involved C75 in the precursor or artificial placement of this Mg2+ into the product structure result in its swift expulsion from the active site. These findings are consistent with a concerted reaction mechanism in which C75 and hydrated Mg2+ act as general base and acid, respectively. Monovalent cations bind to the active site and elsewhere assisted by structurally bridging long-residency water molecules, but are generally delocalized.
- MeSH
- financování organizované MeSH
- hořčík chemie MeSH
- kationty dvojmocné chemie MeSH
- kationty jednomocné chemie MeSH
- konformace nukleové kyseliny MeSH
- molekulární modely MeSH
- molekulární sekvence - údaje MeSH
- RNA katalytická chemie MeSH
- sekvence nukleotidů MeSH
- sodík chemie MeSH
- vazebná místa MeSH
- virus hepatitidy delta enzymologie MeSH
- voda chemie MeSH
- vodíková vazba MeSH
Guanine tetraplexes are a biologically relevant alternative of the Watson and Crick duplex of DNA. It is thought that potassium or other cations present in the cavity between consecutive guanine tetrads are an integral part of the tetraplexes. Here we show using CD spectroscopy that ethanol induces the guanine tetraplexes like or even better than potassium cations. We present examples of ethanol stabilizing guanine tetraplexes even in cases when potassium cations fail to do so. Hence, besides the A-form or Z-form, ethanol stabilizes another conformation of DNA, i.e., the guanine tetraplexes. We discuss the mechanism of the stabilization. Use of ethanol will permit studies of guanine tetraplexes that cannot be induced by potassium cations or other tetraplex-promoting agents. This work demonstrates that a still broader spectrum of nucleotide sequences can fold into guanine tetraplexes than has previously been thought. Aqueous ethanol may better simulate conditions existing in vivo than the aqueous solutions.
- MeSH
- cirkulární dichroismus MeSH
- draslík chemie MeSH
- ethanol chemie MeSH
- financování organizované MeSH
- guanin chemie MeSH
- konformace nukleové kyseliny MeSH
- oligonukleotidy chemická syntéza chemie MeSH
- repetitivní sekvence nukleových kyselin MeSH
- sekvence nukleotidů MeSH
- termodynamika MeSH
- zastoupení bazí MeSH
The availability of ionic liquids (ILs) in wide areas of application often results in the requirement on their determination. The attention is also often focused on the knowledge of hydrophobicity as it plays a key role in the biological effects, in the assessment of environmental risk and in the prediction of the fate of chemicals in the environment and of its influence on retention in RP HPLC. One can get information regarding hydrophobicity and retention mechanism if quantitative structure-retention relationships (QSRRs) are identified. The QSRRs were derived for logarithms of retention factors extrapolated to a pure water (or aqueous buffer) eluent, log k(w), determined for the pyridinium and imidazolium ionic liquid (IL) cations on two C8 (Supelcosil LC-8-DB, Symmetry C8) and two C18 (ACE 5 C18, Symmetry C18) stationary phases with isocratic elution by a mobile phase consisting of acetonitrile/40 mM phosphate buffer. The analyses of ILs were performed at a flow rate of 1 mL min(-1) with UV detection at 218 nm. The QSRRs were derived based on the retention parameters determined experimentally and the structural descriptors of test analytes from molecular modeling. Separations of ILs were obtained with aqueous acetonitrile buffered at pH 3.55 mobile phases. The statistically most significant two-parameter QSRR regression equations related log k(w) to the solvent accessible surface (SAS) of the analytes and the differences in the energies of the highest occupied and the lowest unoccupied molecular orbitals (diffHL). These equations were especially good in case of columns with the highest carbon loads and larger specific surface areas, i.e. Symmetry C18 and Symmetry C8. On the other hand, the column ACE 5 C18 appeared to produce the best quality separations of the ILs studied. The QSRRs derived in the research shed light on the molecular mechanism of HPLC separation of ILs and helped to predict their relative separations.
- MeSH
- chemické modely MeSH
- chromatografie s reverzní fází metody MeSH
- hydrofobní a hydrofilní interakce MeSH
- iontové kapaliny chemie MeSH
- kationty chemie MeSH
- molekulární struktura MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Prostate cancer cells control energy metabolism by chelating intracellular zinc. Thus, zinc delivery has been a popular therapeutic approach for prostate cancer. Here, we propose the use of the membrane-penetrating peptide Novicidin connected to zinc-Schiff base as a carrier vehicle for the delivery of zinc to prostate cells. Mass spectrometry, electrochemistry and spectrophotometry confirmed the formation/stability of this complex and provided insight regarding the availability of zinc for complex interactions. This delivery system showed minor toxicity in normal PNT1A cells and high potency towards PC3 tumor cells. The complex preferentially penetrated PC3 tumor cells in contrast to confinement to the membranes of PNT1A. Furthermore, zinc uptake was confirmed in both cell lines. Molecular analysis was used to confirm the activation of zinc stress (e.g., ZnT-1) and apoptosis (e.g., CASP-1). Our results strongly suggest that the zinc-Schiff base-Novicidin complex has great potential as a novel anticancer drug.
- MeSH
- apoptóza účinky léků MeSH
- exprese genu účinky léků MeSH
- fluorescenční mikroskopie MeSH
- kaspasa 1 metabolismus MeSH
- kationické antimikrobiální peptidy chemie MeSH
- komplexní sloučeniny chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- molekulární konformace MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie MeSH
- proteiny přenášející kationty metabolismus MeSH
- protinádorové látky chemie farmakologie terapeutické užití MeSH
- Schiffovy báze chemie MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- zinek chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Novicidin (NVC), is a membrane-penetrating peptide, which forms a stable complex with Zn-Schiff base with interesting antitumor selectivity. We studied NVC derivatives to determine functional roles of key amino acids in toxicity, helicity, and binding of the Zn-Schiff base complex. Trimmed derivatives highlighted the role of peptide length and helicity in toxicity and membrane penetration. The removal of Lys from position 1 and 2 strongly increases the ability to disrupt the membranes. The trimming of the N-terminal residues significantly increases the stability of peptide helicity enhancing penetrating properties. Gly residue derivatives undermined a role of peptide bending in membrane penetration and toxicity. After the substitution of the central Gly derivatives with Ile or Lys, the peptides retained toxicity. These results illustrate the minor role of central helix bending in NVC toxicity. Binding-site-peptide derivatives identified His residue as the sole Zn-Schiff base binding site and eliminated the role of other aromatic residues.
- MeSH
- glycin chemie MeSH
- kationické antimikrobiální peptidy aplikace a dávkování chemie toxicita MeSH
- konformace proteinů MeSH
- lékové transportní systémy * MeSH
- lidé MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- permeabilita buněčné membrány MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- Schiffovy báze chemie MeSH
- sekvence aminokyselin MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- vazebná místa MeSH
- zinek aplikace a dávkování chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
