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Garcia Guerrero, Estefania, Jose Antonio Pérez Simon, Luis Ignacio Sánchez Abarca, Irene Diaz Moreno, Miguel Angel De la rosa, and Antonio Diaz Quintana. "Molecular Dynamics As a Computational Tool to Study the Immune Reactivity: Identification of Conformational Changes in the Major Histocompatibility Complex." Blood 124, no. 21 (2014): 2735. http://dx.doi.org/10.1182/blood.v124.21.2735.2735.
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Abstract Introduction: The generation of the immune response requires the recognition of peptides presented by the major histocompatibility complex (MHC) through the T cell receptor (TCR). In the hematopoietic transplantation context, T cells (LT) from the donor recognize foreign MHC or own MHC bound to foreign peptides (pMHC), generating an alloimmune response. Currently, the molecular mechanisms of LT alloimmune activation are unknown. In order to analyze the molecular interactions between peptides, MHC and TCR, we have implemented Molecular Dynamics techniques. We have compared immunologically reactive complexes (HLA-A2/TAX/TCR-A6) to non/weakly reactive complexes (HLA-A2/V7R/TCR-A6; HLA-A2/P6A/TCR-A6; HLA-A2/Y8A/TCR-A6). Methods: Starting structure of a reactive complex was downloaded from the PDB database and used to model mutations known to lead to different degrees of immune reactivity. Dynamics simulations were performed and analyzed using the program AMBER version 9. The simulation time was approximately 10 ns. Further analysis was carried out using the script ARO (Díaz-Moreno et al. 2009) in the VMD Tk console. Results: A total of 10 MD trajectories have been reckoned, to simulate the behavior of isolated components of the different pMHC-TCR complexes. Analysis of the fluctuations show that pMHC binding barely restrains TCR motions, affecting mostly to CDR3 loops. Opposite, pMHC displayed substantial changes in its dynamics upon comparing its free versus ternary form (pMHC-TCR). Moreover, we studied the salt-bridges formed between peptide and MHC and we observed a significant loss of salt-bridges in non reactive complexes as compared to reactive ones. Furthermore, the loss of salt-bridges in non reactive complexes affects the electrostatic potential of pMHC complex. According to these results, we next studied the salt-bridges formed between pMHC and TCR. As observed within the binary complex p-MHC, we confirmed a significant loss of salt-bridges in non reactive as compared to reactive complex. Finally, we also analyzed the electrostatic potential of pMHC-TCR complexes and we observed differences between reactive complex and weakly/non reactive complexes. Conclusions: The MHC shows strong changes in its molecular dynamics upon binding to TCR, decreasing its mobility. The “pattern” of salt-bridges between the peptides and the MHC varies depending on the reactivity of the complex, with a loss of salt-bridges in the non-reactive as compared to the reactive ones, which results in change in the electrostatic pattern. In addition, also the number of salt-bridges between pMHC and TCR increases in reactive complexes as compared to non-reactive ones. Disclosures No relevant conflicts of interest to declare.
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Grabowsky, Simon, Allan H. White, Peter C. Healy, et al. "Solid-State NMR, X-Ray Diffraction, and Theoretical Studies of Neutral Mononuclear Molecular Bis(triphenylphosphine)silver(I) Mono-Carboxylate and -Nitrate Systems." Australian Journal of Chemistry 73, no. 6 (2020): 556. http://dx.doi.org/10.1071/ch19616.
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Neutral mononuclear molecular silver(i) carboxylate complexes of the form [(Ph3P)2Ag(O2XY)] with O2XY=O2CCH2Ph, O2CCHPh2, O2CC(CH3)3, O2CCH2C(CH3)3, and O2CCF3 (compounds 1–4 and 5β) have been investigated in the solid state using single-crystal X-ray structure determinations, 1D 31P CPMAS NMR and 2D 31P–31P CPCOSY NMR measurements, and ab initio computational modelling. The results show that these complexes contain P2AgO2 molecular cores with four-coordinate silver in which the carboxylate ligands are weakly bound to the silver atoms via the two oxygen atoms giving rise to unsymmetrical chelate units. Crystal structure determinations and solid-state NMR spectra have also been analysed for the mononuclear molecular silver(i) nitrate complex [(Ph3P)2Ag(O2NO)] (9α) and two polymorphs of its toluene monosolvate (11α, β). In 9α, the two PPh3 ligands are of the same chirality, whereas in 11α, β, they are opposed. The crystalline environments in the polymorphs have been explored by way of Hirshfeld surface analyses, after quantum-mechanical isolated-molecule calculations had shown that although the molecular energies of the experimental geometries of 9α, and 11α, β are significantly different from each other and from the energies of the optimized geometries, the latter, in contrast, do not differ significantly from each other despite the conformational isomerism. It has further been shown using 9α as an example that the energy dependence on variation of the P–Ag–P angle over a range of ~15° is only ~5 kJ mol−1. All this indicates that the forces arising from crystal packing result in significant perturbations in the experimental geometries, but do not alter the stereoisomerism caused by the donor atom array around the Ag atom. In the NMR study, a strong inverse correlation has been found between 1J(107/109Ag,31P) and the Ag–P bond length across all carboxylate and nitrate compounds.
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Krupa, Justyna, Maria Wierzejewska, and Jan Lundell. "Matrix Isolation FTIR and Theoretical Study of Weakly Bound Complexes of Isocyanic Acid with Nitrogen." Molecules 27, no. 2 (2022): 495. http://dx.doi.org/10.3390/molecules27020495.
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Weak complexes of isocyanic acid (HNCO) with nitrogen were studied computationally employing MP2, B2PLYPD3 and B3LYPD3 methods and experimentally by FTIR matrix isolation technique. The results show that HNCO interacts specifically with N2. For the 1:1 stoichiometry, three stable minima were located on the potential energy surface. The most stable of them involves a weak, almost linear hydrogen bond from the NH group of the acid molecule to nitrogen molecule lone pair. Two other structures are bound by van der Waals interactions of N⋯N and C⋯N types. The 1:2 and 2:1 HNCO complexes with nitrogen were computationally tracked as well. Similar types of interactions as in the 1:1 complexes were found in the case of the higher stoichiometry complexes. Analysis of the HNCO/N2/Ar spectra after deposition indicates that the 1:1 hydrogen-bonded complex is prevalent in argon matrices with a small amount of the van der Waals structures also present. Upon annealing, complexes of the 1:2 and 2:1 stoichiometry were detected as well.
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Keefe, C. Dale, and Zuzana Istvankova. "Computational study of proper and improper hydrogen bonding in methanol complexes." Canadian Journal of Chemistry 89, no. 1 (2011): 34–46. http://dx.doi.org/10.1139/v10-155.
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The bulk properties of alcohols, like those of aqueous solutions, are governed mostly by hydrogen bonding; however, in contrast with water molecules, the chemical structure of a simple alcohol such as methanol offers an opportunity to explore the effects of both proper and improper hydrogen bonding on a single hydrogen donor. The presence of the hydroxyl group generally gives rise to a strong proper hydrogen bond, while the methyl group of methanol is likely involved in the weaker improper hydrogen bond, among other weak non-covalent interactions. The effects of the two types of hydrogen bonds on the stability, geometric parameters, and properties of electron density of methanol complexes are examined while considering different geometrical arrangements of the methanol dimer and the binary complexes of methanol with water, acetonitrile, and chloromethane. Subsequently, potential conclusions about the nature of improper hydrogen bonding and the origin of the C–H bond contraction that results upon complex formation are discussed. Quantum theory of atoms in molecules and natural bond orbital methods were used in the analysis; all calculations were performed at the MP2(full)/6-311++G(d,p) level of theory.
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Jimenez-Fabian, Issac, Abraham Jalbout, and Abderahim Boutalib. "Conformational study on the structures and energies of the weakly bound complexes of AlCl3 with diatomic molecules." Open Chemistry 5, no. 4 (2007): 1007–18. http://dx.doi.org/10.2478/s11532-007-0046-4.
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AbstractIn this work we present the results of high level ab initio calculations on weakly bound complexes of aluminium trichloride and hydrogen halides, HX, halogens, X2 and diatomic interhalogens, XY (where X, Y = F, Cl, Br). Based upon these calculations we have predicted that all structures in the staggered conformation (except for Cl3AlFH and Cl3AlClH) are stable minima while those in the eclipsed configurations are transition state structures. In the XH complexes the strength of interaction with the Cl3Al group is FH > ClH > BrH. In the case of X2 species it is Br2 > F2 > Cl2, and finally in the XY (YX) group it is: FBr > ClBr > FCl > BrCl > BrF > ClF.
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Jimenez-Fabian, Isaac, Abraham Jalbout, and Abderahim Boutalib. "Conformational study on the structures and energies of the weakly bound complexes of AlCl3 with diatomic molecules." Open Chemistry 6, no. 1 (2008): 133. http://dx.doi.org/10.2478/s11532-007-0057-1.
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Ritschel, Thomas, Lutz Zülicke, and Philip J. Kuntz. "Cationic Van-der-Waals Complexes: Theoretical Study of Ar2H+ Structure and Stability." Zeitschrift für Physikalische Chemie 218, no. 4 (2004): 377–90. http://dx.doi.org/10.1524/zpch.218.4.377.29196.
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AbstractThe electronic and geometric structure, stability and molecular properties of the cationic van-der-Waals complex Ar2H+ in its ground electronic state are studied by means of two ab-initio quantum-chemical approaches: conventional configuration interaction (multi-reference and coupled-cluster methods) and a diatomics-in-molecules model with ab-initio input data. To ensure consistency between the two approaches, one and the same one-electron atomic basis set (aug-cc-pVTZ by Dunning) is employed in both. The topography of the ground-state potential-energy surface is examined with respect to the nature of the binding and the stability of structures corresponding to stationary points. In accordance with most earlier theoretical work, there are two local minima at linear arrangements: a strongly bound centro-symmetric moiety, (Ar–H–Ar)+, and a weakly bound van-der-Waals complex, Ar···ArH+. These are separated by a low barrier. Only the centro-symmetric molecule is significantly stable (De = 0.68eV) against fragmentation into Ar + ArH+ and should have structural and dynamical relevance. A fairly simple diatomics-in-molecules model taking into account only the few lowest electronic fragment states yields a qualitatively correct description of the ground state but shows quantitative deviations from the more accurate configuration-interaction data in detail. Nevertheless, it should provide a good starting point for the treatment of larger complexes ArnH+ with n > 2.
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Kraevsky, Sergey V., Nikolay A. Barinov, Olga V. Morozova, Vladimir V. Palyulin, Alena V. Kremleva, and Dmitry V. Klinov. "Features of DNA–Montmorillonite Binding Visualized by Atomic Force Microscopy." International Journal of Molecular Sciences 24, no. 12 (2023): 9827. http://dx.doi.org/10.3390/ijms24129827.
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In the present work, complexes of DNA with nano-clay montmorillonite (Mt) were investigated by means of atomic force microscopy (AFM) under various conditions. In contrast to the integral methods of analysis of the sorption of DNA on clay, AFM allowed us to study this process at the molecular level in detail. DNA molecules in the deionized water were shown to form a 2D fiber network weakly bound to both Mt and mica. The binding sites are mostly along Mt edges. The addition of Mg2+ cations led to the separation of DNA fibers into separate molecules, which bound mainly to the edge joints of the Mt particles according to our reactivity estimations. After the incubation of DNA with Mg2+, the DNA fibers were capable of wrapping around the Mt particles and were weakly bound to the Mt edge surfaces. The reversible sorption of nucleic acids onto the Mt surface allows it to be used for both RNA and DNA isolation for further reverse transcription and polymerase chain reaction (PCR). Our results show that the strongest binding sites for DNA are the edge joints of Mt particles.
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Martinez, Arturo I. "Computational Study of Organometallic Structures for Hydrogen Storage, Effects of Ligands." Journal of Nano Research 5 (February 2009): 113–19. http://dx.doi.org/10.4028/www.scientific.net/jnanor.5.113.
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Density functional theory calculations of hydrogen storage capacity for different organometallic structures have been carried out. Complexes involving Sc, Ti and V bound to C4H4, C5H5, C5F5 and B3N3H6 molecules have been considered, and all present a hydrogen storage capability limited by the 18-electron rule. In order to stabilize the complexes, which the 18-electron rule is not completed, additional ligands are considered, namely -H, -CH3, -NH2, -OH and -F. These ligands affect the H2-metal bond; particularly the back donation effect from the metal atom to the * antibonding state of H2 and then its H2 storage capacity.
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Voute, Alexandre, Fabien Gatti, Klaus B. Møller, and Niels E. Henriksen. "Femtochemistry of bimolecular reactions from weakly bound complexes: computational study of the H + H′OD → H′OH + D or HOD + H′ exchange reactions." Physical Chemistry Chemical Physics 23, no. 48 (2021): 27207–26. http://dx.doi.org/10.1039/d1cp04391a.
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The femtochemistry of the reaction between H and HOD, initiated by the photodissociation of HCl in the weakly bound complex (HCl)⋯(HOD), is explored in this computational work. Despite non-reactive scattering is the most probable outcome, H-to-H and H-to-D exchange products can be observed in different proportions whereas no products of the abstraction reaction channel are detectable.
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Zhou, Tian, Santanu Malakar, Steven L. Webb, Karsten Krogh-Jespersen, and Alan S. Goldman. "Polar molecules catalyze CO insertion into metal-alkyl bonds through the displacement of an agostic C-H bond." Proceedings of the National Academy of Sciences 116, no. 9 (2019): 3419–24. http://dx.doi.org/10.1073/pnas.1816339116.
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The insertion of CO into metal-alkyl bonds is the key C-C bond-forming step in many of the most important organic reactions catalyzed by transition metal complexes. Polar organic molecules (e.g., tetrahydrofuran) have long been known to promote CO insertion reactions, but the mechanism of their action has been the subject of unresolved speculation for over five decades. Comprehensive computational studies [density functional theory (DFT)] on the prototypical system Mn(CO)5(arylmethyl) reveal that the polar molecules do not promote the actual alkyl migration step. Instead, CO insertion (i.e. alkyl migration) occurs rapidly and reversibly to give an acyl complex with a sigma-bound (agostic) C-H bond that is not easily displaced by typical ligands (e.g. phosphines or CO). The agostic C-H bond is displaced much more readily, however, by the polar promoter molecules, even though such species bind only weakly to the metal center and are themselves then easily displaced; the facile kinetics of this process are attributable to a hydrogen bonding-like interaction between the agostic C-H bond and the polar promoter. The role of the promoter is to thereby catalyze isomerization of the agostic product of CO insertion to give an η2-C,O-bound acyl product that is more easily trapped than the agostic species. This ability of such promoters to displace a strongly sigma-bound C-H bond and to subsequently undergo facile displacement themselves is without reported precedent, and could have implications for catalytic reactions beyond carbonylation.
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Kutsevol, N., Yu Kuziv, V. Zorin, et al. "Evaluation of a Dextran-Poly(N-Isopropylacrylamide) Copolymer as a Potential Temperature-Dependent Nanocarrier for Photosensitizers with Different Properties." Ukrainian Journal of Physics 65, no. 7 (2020): 638. http://dx.doi.org/10.15407/ujpe65.7.638.
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Thermosensitive polymer poly-N-isopropylacrylamide (PNIPAM) having a conformational transition in the interval of physiological temperatures was discussed last years as a novel drug delivery system. Chlorin e6 (Ce6) is a photosensitizer used in the photodynamic anticancer therapy. The comparative study of the encapsulation of Ce6 and its derivative, dimethylether of chlorine e6 (DME Ce6), into a water-soluble star-like PNIPAM-based copolymer to prevent the aggregation of a photosensitizer in the water medium is carried out. The photophysical properties of the copolymer/photosensitizer complexes as functions of the temperature in the region of the conformational transition of the polymer matrix have been studied and discussed. It is shown that Ce6 at low temperatures interacts weakly with the polymer phase. As a result, the absorption and fluorescence properties of Ce6 in aqueous and polymer solutions are practically identical. Fluorescence characteristics of Ce6 in a copolymer solution remain unchanged, when it is heated, which indicates the lack of a possibility for this sensitizer to bind in the bulk of the polymer phase. Following fluorescence data, all DME Ce6 molecules are bound with the polymer matrix, when a temperature is higher than the Lower Critical Solution Temperature (LCST) of the polymer. The formed complexes are quite stable. In the presence of serum proteins, the molecules of the photosensitizer remain associated for a long time with the polymer. At temperatures below LCST, DME Ce6 is not bound by the polymer. Moreover, the cooling of a solution of DME Ce6/polymer complexes leads to the rapid dissociation of photosensitizer molecules with subsequent aggregation or binding to biological structures in an aqueous medium. The obtained results show that the possibility of using the polymer PNIPAM as a temperature-dependent nanocarrier strongly depends on the properties of the loaded drug.
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Varadwaj, Pradeep R. "Does Oxygen Feature Chalcogen Bonding?" Molecules 24, no. 17 (2019): 3166. http://dx.doi.org/10.3390/molecules24173166.
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Using the second-order Møller–Plesset perturbation theory (MP2), together with Dunning’s all-electron correlation consistent basis set aug-cc-pVTZ, we show that the covalently bound oxygen atom present in a series of 21 prototypical monomer molecules examined does conceive a positive (or a negative) σ-hole. A σ-hole, in general, is an electron density-deficient region on a bound atom M along the outer extension of the R–M covalent bond, where R is the reminder part of the molecule, and M is the main group atom covalently bonded to R. We have also examined some exemplar 1:1 binary complexes that are formed between five randomly chosen monomers of the above series and the nitrogen- and oxygen-containing Lewis bases in N2, PN, NH3, and OH2. We show that the O-centered positive σ-hole in the selected monomers has the ability to form the chalcogen bonding interaction, and this is when the σ-hole on O is placed in the close proximity of the negative site in the partner molecule. Although the interaction energy and the various other 12 characteristics revealed from this study indicate the presence of any weakly bound interaction between the monomers in the six complexes, our result is strongly inconsistent with the general view that oxygen does not form a chalcogen-bonded interaction.
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Schindler, Kevin, Youri Cortat, Miroslava Nedyalkova, et al. "Antimicrobial Activity of Rhenium Di- and Tricarbonyl Diimine Complexes: Insights on Membrane-Bound S. aureus Protein Binding." Pharmaceuticals 15, no. 9 (2022): 1107. http://dx.doi.org/10.3390/ph15091107.
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Antimicrobial resistance is one of the major human health threats, with significant impacts on the global economy. Antibiotics are becoming increasingly ineffective as drug-resistance spreads, imposing an urgent need for new and innovative antimicrobial agents. Metal complexes are an untapped source of antimicrobial potential. Rhenium complexes, amongst others, are particularly attractive due to their low in vivo toxicity and high antimicrobial activity, but little is known about their targets and mechanism of action. In this study, a series of rhenium di- and tricarbonyl diimine complexes were prepared and evaluated for their antimicrobial potential against eight different microorganisms comprising Gram-negative and -positive bacteria. Our data showed that none of the Re dicarbonyl or neutral tricarbonyl species have either bactericidal or bacteriostatic potential. In order to identify possible targets of the molecules, and thus possibly understand the observed differences in the antimicrobial efficacy of the molecules, we computationally evaluated the binding affinity of active and inactive complexes against structurally characterized membrane-bound S. aureus proteins. The computational analysis indicates two possible major targets for this class of compounds, namely lipoteichoic acids flippase (LtaA) and lipoprotein signal peptidase II (LspA). Our results, consistent with the published in vitro studies, will be useful for the future design of rhenium tricarbonyl diimine-based antibiotics.
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Aoyagi, Youko, Elisabeth E. Adderson, Craig E. Rubens, et al. "L-Ficolin/Mannose-Binding Lectin-Associated Serine Protease Complexes Bind to Group B Streptococci Primarily through N-Acetylneuraminic Acid of Capsular Polysaccharide and Activate the Complement Pathway." Infection and Immunity 76, no. 1 (2007): 179–88. http://dx.doi.org/10.1128/iai.00837-07.
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ABSTRACT Group B streptococci (GBS) are the most common cause of neonatal sepsis and meningitis. Most infants who are colonized with GBS at birth do not develop invasive disease, although many of these uninfected infants lack protective levels of capsular polysaccharide (CPS)-specific antibody. The lectin pathway of complement is a potential mechanism for initiating opsonization of GBS with CPS-specific antibody-deficient serum. In this study, we determined whether mannose-binding lectin (MBL)/MBL-associated serine protease (MASP) complexes and L-ficolin/MASP complexes bind to different strains of GBS to activate the lectin pathway, and we identified the molecules recognized by lectins on the GBS surface. We found that MBL did not bind to any GBS examined, whereas L-ficolin bound to GBS cells of many serotypes. L-ficolin binding to GBS cells correlated with the CPS content in serotypes Ib, III (restriction digestion pattern types III-2 and III-3), and V but not with the group B-specific polysaccharide (GBPS) content or with the lipoteichoic acid (LTA) content. L-ficolin bound to purified CPS and GBPS in a concentration-dependent manner but not to purified LTA. All strains to which L-ficolin/MASP complexes bound consumed C4. When N-acetylneuraminic acid (NeuNAc) was selectively removed from GBS cells by treatment with neuraminidase, the reduction in L-ficolin binding was correlated with the amount of NeuNAc removed. Additionally, L-ficolin was able to bind to wild-type strains but was able to bind only weakly to unencapsulated mutants and a mutant strain in which the CPS lacks NeuNAc. We concluded that L-ficolin/MASP complexes bind to GBS primarily through an interaction with NeuNAc of CPS.
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Agamennone, Mariangela, Loriano Storchi, Alessandro Marrone, and Roberto Paciotti. "Hampering the early aggregation of PrP-E200K protein by charge-based inhibitors: a computational study." Journal of Computer-Aided Molecular Design 35, no. 6 (2021): 751–70. http://dx.doi.org/10.1007/s10822-021-00393-7.
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AbstractA multilayered computational workflow was designed to identify a druggable binding site on the surface of the E200K pathogenic mutant of the human prion protein, and to investigate the effect of the binding of small molecules in the inhibition of the early aggregation of this protein. At this purpose, we developed an efficient computational tool to scan the molecular interaction properties of a whole MD trajectory, thus leading to the characterization of plausible binding regions on the surface of PrP-E200K. These structural data were then employed to drive structure-based virtual screening and fragment-based approaches to the seeking of small molecular binders of the PrP-E200K. Six promising compounds were identified, and their binding stabilities were assessed by MD simulations. Therefore, analyses of the molecular electrostatic potential similarity between the bound complexes and unbound protein evidenced their potential activity as charged-based inhibitors of the PrP-E200K early aggregation.
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Altun, Bleda, and Trindle. "Production of Carbamic Acid Dimer from Ammonia-Carbon Dioxide Ices: Matching Observed and Computed IR Spectra." Life 9, no. 2 (2019): 34. http://dx.doi.org/10.3390/life9020034.
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The production of complex molecules in ammonia–carbon dioxide ices is presumed to pass through species of formula H3N:CO2 with further addition of ammonia and carbon dioxide. One possible landmark, carbamic acid, H2NCOOH, has been implicated among the products of warming and irradiation of such ices. Experimental study of the IR spectra of residues has suggested the presence of related species, including weakly bound 1:1 and 2:1 complexes of ammonia with carbon dioxide, zwitterionic carbamic acid, ammonium carbamate, and the dimer of carbamic acid. We computed the energetics and vibrational spectra of these species as well as the complex between ammonia and carbamic acid for gas and condensed phases. By means of a new spectrum-matching scoring between computed and observed vibrational spectra, we infer species that are most probably present. The leading candidates are ammonium carbamate, the carbamic acid–ammonia complex, and the carbamic acid dimer.
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Lloyd, Austin, Helen Moylan, and Joseph McDouall. "Modelling the Effect of Zero-Field Splitting on the 1H, 13C and 29Si Chemical Shifts of Lanthanide and Actinide Compounds." Magnetochemistry 5, no. 1 (2019): 3. http://dx.doi.org/10.3390/magnetochemistry5010003.
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The prediction of paramagnetic NMR (pNMR) chemical shifts in molecules containing heavy atoms presents a significant challenge to computational quantum chemistry. The importance of meeting this challenge lies in the central role that NMR plays in the structural characterisation of chemical systems. Hence there is a need for reliable assignment and prediction of chemical shifts. In a previous study [Trends in Physical Chemistry, 17, 25–57, (2017)] we looked at the computation of pNMR chemical shifts in lanthanide and actinide complexes using a spin Hamiltonian approach. In that study we were principally concerned with molecules with S = 1/2 ground states. In the present work we extend that study by looking at the effect of zero field splitting (ZFS) for six complexes with S = 3/2 ground states. It is shown that the inclusion of ZFS can produce substantial shifts in the predicted chemical shifts. The computations presented are typically sufficient to enable assignment of experimental spectra. However for one case, in which the peaks are closely clustered, the inclusion of ZFS re-orders the chemical shifts making assignment quite difficult. We also observe, and echo, the previously reported importance of including the paramagnetic spin-orbit hyperfine interaction for 13 C and 29 Si atoms, when these are directly bound to a heavy element and thus subject to heavy-atom-light-atom effects. The necessary computations are very demanding, and more work is needed to find theoretical and computational approaches that simplify the evaluation of this term. We discuss the computation of each term required in the spin Hamiltonian. The systems we study in this work are restricted to a single heavy atom ion (one Nd(III) and five U(III) complexes), but typify some of the computational complexity encountered in lanthanide and actinide containing molecules.
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Pérez de la Lastra, José Manuel, Celia Andrés-Juan, Francisco J. Plou, and Eduardo Pérez-Lebeña. "Theoretical Three-Dimensional Zinc Complexes with Glutathione, Amino Acids and Flavonoids." Stresses 1, no. 3 (2021): 123–41. http://dx.doi.org/10.3390/stresses1030011.
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Zinc plays an important role in the regulation of many cellular functions; it is a signaling molecule involved in the transduction of several cascades in response to intra and extracellular stimuli. Labile zinc is a small fraction of total intracellular zinc, that is loosely bound to proteins and is easily interchangeable. At the cellular level, several molecules can bind labile zinc and promote its passage across lipophilic membranes. Such molecules are known as ionophores. Several of these compounds are known in the scientific literature, but most of them can be harmful to human health and are therefore not allowed for medical use. We here performed a theoretical three-dimensional study of known zinc ionophores, together with a computational energetic study and propose that some dietary flavonoids, glutathione and amino acids could form zinc complexes and facilitate the transport of zinc, with the possible biological implications and potential health benefits of these natural compounds. The study is based on obtaining a molecular conformational structure of the zinc complexes with the lowest possible energy content. The discovery of novel substances that act as zinc ionophores is an attractive research topic that offers exciting opportunities in medicinal chemistry. We propose that these novel complexes could be promising candidates for drug design to provide new solutions for conditions and diseases related to zinc deficiency or impairment derived from the dysregulation of this important metal.
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Fraschetti, Caterina, Marco Pierini, Claudio Villani, Francesco Gasparrini, Antonello Filippi, and Maurizio Speranza. "Gas-phase structure and relative stability of proton-bound homo- and heterochiral clusters of tetra-amide macrocycles with amines." Collection of Czechoslovak Chemical Communications 74, no. 2 (2009): 275–97. http://dx.doi.org/10.1135/cccc2008155.
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The structure, stability, and CID pattern of proton-bound homochiral and heterochiral complexes, formed in the gas phase by the combination of two molecules of a chiral macrocyclic tetra-amide and an amine B, i.e. CH3NH2, (CH3)2NH, or (S)-(–)-1-phenylethylamine, have been examined by ESI-ITMS-CID mass spectrometry. With B = CH3NH2, the CID pattern is characterized by the predominant loss of B, accompanied by a much less extensive release of one tetra-amide molecule. With (S)-(–)-1-phenylethylamine, loss of a tetra-amide molecule efficiently competes with loss of B. Finally, with (CH3)2NH, loss of a tetra-amide molecule predominates over loss of B. No appreciable isotope and chiral guest configuration effects have been detected in the fragmentation of the homochiral complexes. A distinct configurational effect has been appreciated in the CID of the homo- and the heterochiral complexes with all amines used. The results of this study have been discussed in the light of semi-empirical computational evidence. The differences in the CID patterns of the homo- and the heterochiral complexes have been rationalized in terms of structural factors and of the basicity of amine B.
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Sang, Peng, Yong-Qin Chen, Meng-Ting Liu, et al. "Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants." International Journal of Molecular Sciences 23, no. 23 (2022): 14796. http://dx.doi.org/10.3390/ijms232314796.
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To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBDWT-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBDOMIs) feature increased global structural fluctuations when compared with RBDWT. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBDOMIs than RBDWT, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBDBA.4/5) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBDBA.4/5 results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2.
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Rahi, Sahand J., Peter Virnau, Leonid A. Mirny, and Mehran Kardar. "Predicting transcription factor specificity with all-atom models." Nucleic Acids Research 36, no. 19 (2008): 6209–17. http://dx.doi.org/10.1093/nar/gkn589.
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Abstract The binding of a transcription factor (TF) to a DNA operator site can initiate or repress the expression of a gene. Computational prediction of sites recognized by a TF has traditionally relied upon knowledge of several cognate sites, rather than an ab initio approach. Here, we examine the possibility of using structure-based energy calculations that require no knowledge of bound sites but rather start with the structure of a protein–DNA complex. We study the PurR Escherichia coli TF, and explore to which extent atomistic models of protein–DNA complexes can be used to distinguish between cognate and noncognate DNA sites. Particular emphasis is placed on systematic evaluation of this approach by comparing its performance with bioinformatic methods, by testing it against random decoys and sites of homologous TFs. We also examine a set of experimental mutations in both DNA and the protein. Using our explicit estimates of energy, we show that the specificity for PurR is dominated by direct protein–DNA interactions, and weakly influenced by bending of DNA.
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Gotch, Albert J., R. Nathan Pribble, Frederick A. Ensminger та Timothy S. Zwier. "The Spectroscopy and Photophysics of π Hydrogen-Bonded Complexes: Benzene–CHCl3". Laser Chemistry 13, № 3-4 (1994): 187–205. http://dx.doi.org/10.1155/1994/41604.
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A vibronic level study of the spectroscopy and photophysics of the C6H6–CHCl3 complex has been carried out using a combination of laser-induced fluorescence and resonant two-photon ionization (R2PI). In C6H6-CHCl3, the S1–S0 origin remains forbidden while the 1610 transition is weakly induced. Neither 610 nor 1610 are split by the presence of the CHCl3 molecule. On this basis, a C3vstructure is deduced for the complex, placing CHCl3 on the six-fold axis of benzene. The large blue-shift of the complex’s absorption relative to benzene (+178 cm–1) and the efficient fragmentation of the complex following one-color R2PI reflect a hydrogen-bonded orientation for CHCl3 relative to benzene’ π cloud. Dispersed fluorescence scans place a firm upper bound on the ground state binding energy of the complex of 2,024 cm–1. Both the 61and 61 11 levels do not dissociate on the time-scale of the S1 fluorescence and show evidence of extensive state mixing with van der Waals’ levels primarily built on the 00 level of benzene. The C6H6–(CHCl3)2 cluster shows extensive intermolecular structure beginning at +84 cm–1, a strong origin transition, and splitting of 61. A structure which places both CHCl3 molecules on the same side of the benzene ring is suggested on this basis. The vibronic level scheme used to deduce the structure of C6H6–CHCl3 is tested against previous data on other C6H6–X complexes. The scheme is found to be capable, in favorable cases, of deducing the structures of C6H6–X complexes based purely on vibronic level data. Finally, the results on C6H6–CHCl3 are compared with those on C6H6–HCl and C6H6-H2O to evaluate the characteristics of the n hydrogen bond.
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Lee, Calvin W. Z., M. Qadri E. Mubarak, Anthony P. Green та Sam P. de Visser. "How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study". International Journal of Molecular Sciences 21, № 19 (2020): 7133. http://dx.doi.org/10.3390/ijms21197133.
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Heme peroxidases have important functions in nature related to the detoxification of H2O2. They generally undergo a catalytic cycle where, in the first stage, the iron(III)–heme–H2O2 complex is converted into an iron(IV)–oxo–heme cation radical species called Compound I. Cytochrome c peroxidase Compound I has a unique electronic configuration among heme enzymes where a metal-based biradical is coupled to a protein radical on a nearby Trp residue. Recent work using the engineered Nδ-methyl histidine-ligated cytochrome c peroxidase highlighted changes in spectroscopic and catalytic properties upon axial ligand substitution. To understand the axial ligand effect on structure and reactivity of peroxidases and their axially Nδ-methyl histidine engineered forms, we did a computational study. We created active site cluster models of various sizes as mimics of horseradish peroxidase and cytochrome c peroxidase Compound I. Subsequently, we performed density functional theory studies on the structure and reactivity of these complexes with a model substrate (styrene). Thus, the work shows that the Nδ-methyl histidine group has little effect on the electronic configuration and structure of Compound I and little changes in bond lengths and the same orbital occupation is obtained. However, the Nδ-methyl histidine modification impacts electron transfer processes due to a change in the reduction potential and thereby influences reactivity patterns for oxygen atom transfer. As such, the substitution of the axial histidine by Nδ-methyl histidine in peroxidases slows down oxygen atom transfer to substrates and makes Compound I a weaker oxidant. These studies are in line with experimental work on Nδ-methyl histidine-ligated cytochrome c peroxidases and highlight how the hydrogen bonding network in the second coordination sphere has a major impact on the function and properties of the enzyme.
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Piepenbrink, Kurt H., Oleg Y. Borbulevych, Ruth F. Sommese, et al. "Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner." Biochemical Journal 423, no. 3 (2009): 353–61. http://dx.doi.org/10.1042/bj20090732.
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TCR (T-cell receptor) recognition of antigenic peptides bound and presented by MHC (major histocompatibility complex) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide–MHC complexes weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Furthermore, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. In the present study, we examined how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the Tax peptide [HTLV (human T-cell lymphotropic virus)-1 Tax11-19] enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with the A6 TCR independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, we probed the mechanism of fluorine's effect on TCR binding and we conclude that our results were most consistent with a ‘polar hydrophobicity’ mechanism, rather than a purely hydrophobic- or electrostatic-based mechanism. This finding should have an impact on other attempts to alter molecular recognition with fluorine.
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Braasch-Turi, Margaret M., Jordan T. Koehn, and Debbie C. Crans. "Chemistry of Lipoquinones: Properties, Synthesis, and Membrane Location of Ubiquinones, Plastoquinones, and Menaquinones." International Journal of Molecular Sciences 23, no. 21 (2022): 12856. http://dx.doi.org/10.3390/ijms232112856.
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Lipoquinones are the topic of this review and are a class of hydrophobic lipid molecules with key biological functions that are linked to their structure, properties, and location within a biological membrane. Ubiquinones, plastoquinones, and menaquinones vary regarding their quinone headgroup, isoprenoid sidechain, properties, and biological functions, including the shuttling of electrons between membrane-bound protein complexes within the electron transport chain. Lipoquinones are highly hydrophobic molecules that are soluble in organic solvents and insoluble in aqueous solution, causing obstacles in water-based assays that measure their chemical properties, enzyme activities and effects on cell growth. Little is known about the location and ultimately movement of lipoquinones in the membrane, and these properties are topics described in this review. Computational studies are particularly abundant in the recent years in this area, and there is far less experimental evidence to verify the often conflicting interpretations and conclusions that result from computational studies of very different membrane model systems. Some recent experimental studies have described using truncated lipoquinone derivatives, such as ubiquinone-2 (UQ-2) and menaquinone-2 (MK-2), to investigate their conformation, their location in the membrane, and their biological function. Truncated lipoquinone derivatives are soluble in water-based assays, and hence can serve as excellent analogs for study even though they are more mobile in the membrane than the longer chain counterparts. In this review, we will discuss the properties, location in the membrane, and syntheses of three main classes of lipoquinones including truncated derivatives. Our goal is to highlight the importance of bridging the gap between experimental and computational methods and to incorporate properties-focused considerations when proposing future studies relating to the function of lipoquinones in membranes.
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Alkorta, Ibon, José Elguero, Josep M. Oliva-Enrich, Manuel Yáñez, Otilia Mó, and M. Merced Montero-Campillo. "The Importance of Strain (Preorganization) in Beryllium Bonds." Molecules 25, no. 24 (2020): 5876. http://dx.doi.org/10.3390/molecules25245876.
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In order to explore the angular strain role on the ability of Be to form strong beryllium bonds, a theoretical study of the complexes of four beryllium derivatives of orthocloso-carboranes with eight molecules (CO, N2, NCH, CNH, OH2, SH2, NH3, and PH3) acting as Lewis bases has been carried out at the G4 computational level. The results for these complexes, which contain besides Be other electron-deficient elements, such as B, have been compared with the analogous ones formed by three beryllium salts (BeCl2, CO3Be and SO4Be) with the same set of Lewis bases. The results show the presence of large and positive values of the electrostatic potential associated to the beryllium atoms in the isolated four beryllium derivatives of ortho-carboranes, evidencing an intrinsically strong acidic nature. In addition, the LUMO orbital in these systems is also associated to the beryllium atom. These features led to short intermolecular distances and large dissociation energies in the complexes of the beryllium derivatives of ortho-carboranes with the Lewis bases. Notably, as a consequence of the special framework provided by the ortho-carboranes, some of these dissociation energies are larger than the corresponding beryllium bonds in the already strongly bound SO4Be complexes, in particular for N2 and CO bases. The localized molecular orbital energy decomposition analysis (LMOEDA) shows that among the attractive terms associated with the dissociation energy, the electrostatic term is the most important one, except for the complexes with the two previously mentioned weakest bases (N2 and CO), where the polarization term dominates. Hence, these results contribute to further confirm the importance of bending on the beryllium environment leading to strong interactions through the formation of beryllium bonds.
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Mézière, C., M. Viguier, H. Dumortier, et al. "In vivo T helper cell response to retro-inverso peptidomimetics." Journal of Immunology 159, no. 7 (1997): 3230–37. http://dx.doi.org/10.4049/jimmunol.159.7.3230.
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Abstract Peptide analogues containing reversed peptide bonds between each residue along the peptide sequence (retro-inverso modification) have been analyzed for their antigenic and in vivo immunogenic properties in the MHC II and Th cell response context. Two antigenic peptides were selected for this study, namely peptide 103-115 of poliovirus VP1, which is involved in the production of Abs that neutralize the infectivity of the virus, and peptide 435-446 from the third constant region of mouse heavy chain IgG2a allopeptide gamma 2ab, which mimics a corneal Ag implicated in autoimmune keratitis. In a competition assay performed in vitro using reference hybridomas of known MHC class II restriction, both retro-inverso analogues bound (although more weakly in our test) to I-Ad and/or I-Ed class II molecules. However, in both cases, this lower affinity was apparently largely compensated in vivo, as a T cell response (with IL-2 secretion), equivalent to that obtained with the wild-type peptides, was observed following immunization of BALB/c mice with the retro-inverso analogues. Moreover, these T cells proliferated and produced IL-2 in response to the cognate peptides. It is concluded that the T cell receptors of T cells primed in vivo with the retro-inverso analogues readily cross-react with parent and retro-inverso analogue-MHC complexes. The approach of using pseudopeptides containing changes involving the backbone, and not the orientation of side chains, may thus be promising to design potent immunogens for class II-restricted T cells.
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Lishko, Valeryi K., and Tatiana P. Ugarova. "Evidence That Fibrinogen Inhibits Leukocyte Adhesion to Fibrin Clot and Immobilized Fibrinogen by Binding to the Substrate but Not to Integrins." Blood 106, no. 11 (2005): 2631. http://dx.doi.org/10.1182/blood.v106.11.2631.2631.
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Abstract The recruitment of phagocytic leukocytes to sites of injured vessel wall plays an important role in thrombus remodeling during normal vascular repair and in the pathophysiology of thrombosis. Fibrin and fibrinogen, present in the thrombus, are potent adhesive substrates for neutrophils and monocytes. They support cellular attachment by binding cell surface receptors that belong to the β2 subfamily of integrins. Adhesive interactions of neutrophils and monocytes with polymerized fibrin and insoluble fibrinogen matrix in vivo occur in the presence of high concentrations of circulating plasma fibrinogen (~2–4 mg/ml). One important property of fibrinogen that would have a major bearing on leukocyte adhesion is its capacity to form complexes with fibrin. Therefore, by virtue of its binding to the fibrin clot and/or immobilized fibrinogen, soluble plasma fibrinogen can influence leukocyte adhesion to these substrates. In this study, the possibility that soluble fibrinogen could protect fibrin from adhesion of leukocytes was examined. Fibrinogen was an efficient inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated non-covalently and weakly with fibrin(ogen) substrates. Consequently, leukocyte integrins that engage fibrinogen molecules loosely bound to the fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various β2-integrin bearing cells and performed under static and flow conditions. Furthermore, surface plasmon resonance studies, undertaken to determine the Kd of fibrinogen-fibrin interactions under flow conditions, indicated that fibrinogen formed complexes with fibrin(ogen) with micromolar affinities. Thus, these findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion. They also imply that the anti-adhesive effect of fibrinogen may protect the thrombus from an excessive leukocyte accumulation and premature dissolution at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss.
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Bowmaker, Graham A., Dip Singh Gill, Brian W. Skelton, Neil Somers, and Allan H. White. "Syntheses, Structures and Vibrational Spectroscopy Studies of Copper(I) Perchlorate : Benzonitrile Adducts (1 : n) of n = 2, 3, 4, 5 Stoichiometry." Zeitschrift für Naturforschung B 59, no. 11-12 (2004): 1307–13. http://dx.doi.org/10.1515/znb-2004-11-1249.
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Abstract Syntheses and room-temperature single crystal X-ray structure determinations are recorded for an array of complexes formed between copper(I) perchlorate and benzonitrile of CuClO4 : PhCN (1:n) stoichiometry. Copper(I) perchlorate crystallized from neat benzonitrile solution yields a 1:5 CuClO4 : PhCN adduct, shown by the X-ray study to be of the form [Cu(NCPh)4](ClO4). PhCN, and, on recrystallization from dichloromethane, the 1:4 adduct, shown to be [Cu(NCPh)4](ClO4), the copper(I) atom in both the n = 4,5 adducts being in a quasi-tetrahedral four-coordinate environment, < Cu−N > 1.99 Å . Heating of either of the above materials under vacuum to 70 - 80◦ or 85 - 90 ◦C (Care!) yields 1:3 and 1:2 adducts respectively which may be crystallized from dichloromethane. The 1:3 adduct is shown to be of the form [(PhCN)3Cu(OClO3)], the CuN3 array quasi-trigonal planar (Σ N-Cu-N 358.0 ◦; Cu-N 1.906(4)-1.958(4), <> 1.93 Å ), with a long unidentate perchlorate oxygen approach (Cu. . .O 2.404(4) Å). The 1:2 adduct comprises a pair of quasi-linear [(PhCN)Cu(NCPh)] moieties (Cu-N 1.884(6), 1.866(5) Å ; N-Cu-N 158.6(3)◦] linked about an inversion centre by a pair of oxygen atoms from centrosymmetrically related perchlorate groups, so that a weakly bound fourmembered Cu(μ-O)2Cu central ring is obtained (Cu. . .O 2.445(4), 2.502(6) Å ). The structural data provide a basis for a comprehensive vibrational spectroscopic study across the whole array. These spectra show features that can be attributed to the structural changes that are observed with the change in the number of benzonitrile molecules in the compounds. The vibrational spectra of the acetonitrile complex [Cu(NCMe)4](ClO4) have also been recorded and used to assist in the assignment of the spectra of the various stoichiometries of the benzonitrile compounds.
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Raoufi, Mojgan, Wenhua Zhou, Enriqueta Guinto, et al. "A Sensitive Enzyme-Linked Assay of ADAMTS13 Antibodies for Diagnosis of TTP." Blood 106, no. 11 (2005): 553. http://dx.doi.org/10.1182/blood.v106.11.553.553.
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Abstract Thrombotic thrombocytopenic purpura (TTP), a serious disorder characterized by the development of VWF-platelet rich thrombi in the arterioles and capillaries, requires reliable diagnostic assays for optimal management of the patients. Simple, reliable assays of ADAMTS13 inhibitors or antibodies are not yet widely available. To develop an ELISA for antibodies of ADAMTS13, we analyze the levels of patient IgG bound to immobilized recombinant ADAMTS13 in a microtiter plate format. The mean (±SD) IgG binding value is 5.1 ± 1.5 arbitrary units (AU)/mL among a group of 36 normal subjects and is 5.3 ± 2.7 AU/mL among 31 random patients (P &gt; 0.1). Two (5%) of the normal group and 2 (6%) of the random group are outliers. When applied to patients with thrombotic microangiopathy, this assay yields IgG binding values ranging from 2.0 – 58.3 (median = 5.4) AU/mL in a group of 40 subjects with other thrombotic microangiopathy and 10.1 - &gt; 60.0 (median 49.0) AU/mL in a group of 56 patients with acute TTP. Excluding 2 (5%) outlying samples, the mean (±SD) for the “other TM” group is 5.9 ±2.5 AU/mL, which is not different from the values of the normal and random subjects. In contrast, the IgG binding values are &gt; 10.0 AU/mL in each of the acute TTP patients. Furthermore, heating the plasma samples at 56oC, presumably by dissociating ADAMTS13 from immune complexes, increases IgG binding of 4 weakly positive TTP samples from 10.1 – 12.7 to 28.3 – 154.3 AU/mL. Addition of native ADAMTS13 lacking the tag sequences decreases the binding of TTP IgG to 40% ± 20% of control, but does not affect the binding of 6 outlying non-TTP IgG (120% ± 20% vs. control, P &lt; 0.001), suggesting that the IgG of non-TTP samples do not recognize ADAMTS13. In summary, the ELISA for ADAMTS13 antibodies is highly sensitive for detection of ADAMTS13 antibodies. A subset of the general population contains IgG molecules that react with the recombinant ADAMTS13 fusion protein but not with native ADAMTS13. Blocking with native ADAMTS13 enhances the specificity of the assay for TTP. Figure Left: Binding of IgG to immobilized rADAMTS13-FLAG/His in four groups of study subjects. Right: Suppression of IgG binding by untagged ADAMTS13 in TTP but not in non-TTP samples. Figure. Left: Binding of IgG to immobilized rADAMTS13-FLAG/His in four groups of study subjects. . / Right: Suppression of IgG binding by untagged ADAMTS13 in TTP but not in non-TTP samples.
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Chen, Yingqian, and Sergei Manzhos. "Li Storage on TCNE and TCNE-(Doped)-Graphene Complexes: a Computational Study." MRS Proceedings 1679 (2014). http://dx.doi.org/10.1557/opl.2014.849.
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ABSTRACTLi attachment to free tetracyanoethylene (TCNE) molecules and TCNE adsorbed on doped graphene is studied using density functional theory. While TCNE is adsorbed only weakly on ideal graphene, we identified a configuration in which TCNE is chemisorbed on Al-doped graphene via its C atom and a surface oxygen atom. Up to four Li atoms can be stored on both free and adsorbed TCNE with binding energies stronger than cohesive energy of the Li metal. TCNE immobilized on the conducting graphene-based substrate could therefore become an efficient anode material for organic Li ion batteries.
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Rivero, Maribel, Sergio Boneta, Nerea Novo, Adrián Velázquez-Campoy, Victor Polo, and Milagros Medina. "Riboflavin kinase and pyridoxine 5′-phosphate oxidase complex formation envisages transient interactions for FMN cofactor delivery." Frontiers in Molecular Biosciences 10 (March 28, 2023). http://dx.doi.org/10.3389/fmolb.2023.1167348.
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Enzymes catalysing sequential reactions have developed different mechanisms to control the transport and flux of reactants and intermediates along metabolic pathways, which usually involve direct transfer of metabolites from an enzyme to the next one in a cascade reaction. Despite the fact that metabolite or substrate channelling has been widely studied for reactant molecules, such information is seldom available for cofactors in general, and for flavins in particular. Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) act as cofactors in flavoproteins and flavoenzymes involved in a wide range of physiologically relevant processes in all type of organisms. Homo sapiens riboflavin kinase (RFK) catalyses the biosynthesis of the flavin mononucleotide cofactor, and might directly interplay with its flavin client apo-proteins prior to the cofactor transfer. Non-etheless, none of such complexes has been characterized at molecular or atomic level so far. Here, we particularly evaluate the interaction of riboflavin kinase with one of its potential FMN clients, pyridoxine-5′-phosphate oxidase (PNPOx). The interaction capacity of both proteins is assessed by using isothermal titration calorimetry, a methodology that allows to determine dissociation constants for interaction in the micromolar range (in agreement with the expected transient nature of the interaction). Moreover, we show that; i) both proteins become thermally stabilized upon mutual interaction, ii) the tightly bound FMN product can be transferred from RFK to the apo-form of PNPOx producing an efficient enzyme, and iii) the presence of the apo-form of PNPOx slightly enhances RFK catalytic efficiency. Finally, we also show a computational study to predict likely RFK-PNPOx binding modes that can envisage coupling between the FMN binding cavities of both proteins for the potential transfer of FMN.
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Kalmankar, Neha V., Bhuvaneshwari Rajendrakumar Gehi та Ramanathan Sowdhamini. "Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations". Frontiers in Molecular Biosciences 9 (30 вересня 2022). http://dx.doi.org/10.3389/fmolb.2022.986704.
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Aggregation of β-amyloid (Aβ) peptide is one of the hallmarks of Alzheimer’s disease (AD) which results in chronic and progressive neurodegeneration of the brain. A recent study by our group have shown the ability of cyclic disulfide-rich peptides (“cyclotides”) isolated from a medicinal plant, Clitoria ternatea, to inhibit the aggregation of Aβ peptides and reduce oxidative stress caused by reactive oxygen species using in vivo models of transgenic Caenorhabditis elegans. In the present study, through extensive computational docking and multi-ns molecular dynamics (MD) simulation, we evaluated if cyclotides can stably bind to Aβ molecules and/or destabilize the Aβ fibril by preventing conformational changes from α-helical to β-sheet rich structures. We demonstrate that cyclotides bind effectively and stably to different forms of Aβ structures via hydrogen bonding and hydrophobic interactions. One of the conserved hydrophobic interface residues, Tyr10 was mutated to Ala and the impact of this virtual mutation was estimated by additional MD simulations for the wild-type (WT) and mutant protein-peptide complexes. A detailed MD simulation analyses revealed that cyclotides form hydrogen bonds with the toxic amyloid assemblies thereby weakening the inter-strand hydrogen bonds between the Aβ peptide. The φ-ѱ distribution map of residues in the cyclotide binding pocket that ideally adopt β-sheet conformation show deviation towards right-handed ɑ-helical (ɑR) conformation. This effect was similar to that observed for the Tyr10Ala mutant and doubly so, for the cyclotide bound form. It is therefore possible to hypothesise that the opening up of amyloid β-sheet is due to an unfolding process occurring in the Aβ caused by cyclotide binding and inhibition. Our current findings provide novel structural insights on the mode of interaction between cyclotides and Aβ fibrils and describe their anti-amyloid aggregation potential. This sheds light on the future of cyclotide-based drug design against protein aggregation, a hallmark event in many neurodegenerative diseases.