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At least 19 recordsLinked to original sources
PubMed1991

Chemical models for the chemical nature of endogenous digitalis.

The inability or the capacity to promote the phosphorylation of Na+/K(+)-transporting ATPase (Na/K-ATPase) from [32P]Pi is shown to differentiate between mechanistically digitalis-unlike and digitalis-like inhibitors of this enzyme known to be the receptor for all digitalis actions. A negative or positive response in the phosphorylation promotion assay introduced here appears thus to be suitable to diagnose the chemical species in the isolates of animal origin related to the putative endogenous digitalis. Various digitalis-congeneric C/D-cis steroids, progesterone-congeneric C/D-trans steroids and the Erythrophleum alkaloid cassaine promote the enzyme phosphorylation and show a similar pattern of discrimination between three Na/K-ATPase variants. Thus, their cyclopentanoperhydrophenanthrene or perhydrophenanthrene nuclei appear to serve as the minimal pharmacophoric lead structures for bimolecular recognition and to represent chemical models for the chemical nature of endogenous digitalis. Specifically, the hormonal C/D-trans steroids could provide the basic skeleton in endogenous digitalis biosynthesis.

Animals↗
PubMed2005

A computationally feasible quantum chemical model for 13C NMR chemical shifts of PCB-derived carboxylic acids.

Two quantum chemical models have been derived for the prediction of 13C NMR chemical shifts of novel PCB acids obtained from PCBs by catalytic carbonylation. 13C isotropic shielding constants were calculated employing the GIAO (gauge-independent atomic orbital) method with density functional theory (DFT). The best results were obtained by cluster calculations, which took the solvent effects into account properly. In this approach, a solvent molecule (acetone) was attached by a hydrogen bond to every hydrogen atom present in a PCB acid, and the geometry of the molecular cluster was optimized employing the AM1 method. For 158 chemical shifts, the cross-validated standard error was 2.8 ppm and the cross-validated correlation coefficient was 0.94.

Carbon Isotopes↗
PubMed2002

Synthesis of (+/-)-madindolines and chemical models. Studies of chemical reactivity.

[reaction: see text] The madindolines are believed to inhibit cytokine signaling through the gp130 receptor. Model compounds of madindolines were synthesized and tested for thiol reactivity. The heterocyclic moiety of madindoline was shown to form thiol adducts via the Savige-Fontana reaction. The enedione moiety was found to be unreactive toward simple thiols unless the quaternary center was removed. Using the powerful Moore reaction, we have synthesized (+/-)-madindoline A and B in 11 steps.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2006

What I have learned by using chemical model systems to study biomolecular structure and interactions.

Chemical model systems provide valuable insights into biomolecular structure and interactions by allowing researchers to simplify, isolate, and manipulate aspects of the complex molecular machinery of living systems. This perspective describes my laboratory's design, synthesis, and study of chemical model systems that fold and self-assemble like proteins and elucidates the insights that have come from studying these systems. Many of these studies have focused on protein beta-sheets, which exhibit fascinating intra- and intermolecular interactions and play important roles in protein folding, aggregation, and molecular recognition.

Dimerization↗
PubMed2004

Quantum chemical modeling of the GTP hydrolysis by the RAS-GAP protein complex.

We present results of the modeling for the hydrolysis reaction of guanosine triphosphate (GTP) in the RAS-GAP protein complex using essentially ab initio quantum chemistry methods. One of the approaches considers a supermolecular cluster composed of 150 atoms at a consistent quantum level. Another is a hybrid QM/MM method based on the effective fragment potential technique, which describes interactions between quantum and molecular mechanical subsystems at the ab initio level of the theory. Our results show that the GTP hydrolysis in the RAS-GAP protein complex can be modeled by a substrate-assisted catalytic mechanism. We can locate a configuration on the top of the barrier corresponding to the transition state of the hydrolysis reaction such that the straightforward descents from this point lead either to reactants GTP+H(2)O or to products guanosine diphosphate (GDP)+H(2)PO(4)(-). However, in all calculations such a single-step process is characterized by an activation barrier that is too high. Another possibility is a two-step reaction consistent with formation of an intermediate. Here the Pgamma-O(Pbeta) bond is already broken, but the lytic water molecule is still in the pre-reactive state. We present arguments favoring the assumption that the first step of the GTP hydrolysis reaction in the RAS-GAP protein complex may be assigned to the breaking of the Pgamma-O(Pbeta) bond prior to the creation of the inorganic phosphate.

Crystallography, X-Ray↗
PubMed1997

Electron affinities of p-benzoquinone, p-benzoquinone imine and p-benzoquinone diimine, and spin densities of their p-benzosemiquinones computed by several quantum chemical models.

Restricted and unrestricted (U) Hartree-Fock (HF), second-order Møller-Plesset perturbation (MP2), density functional (DF), hybrid HF/DF and semiempirical (half-electron (HE) method) models have been used to calculate adiabatic electron affinities (EAad values) of p-benzoquinone (I), p-benzoquinone imine (VI) and p-benzoquinone diimine (XI), as well as expectation values ( ) and spin density distributions in the radical anions of I, VI and XI. The AM1/AM1-HE and ab initio calculated structures are found to be in accord with each other. The ROHF/6-31G(d) method gave the poorest EAad result. The UHF and UMP2 wave functions were found to be substantially spin contaminated (for the radicals) and the accuracies of the EAad values calculated were also poor. The use of molecular energies obtained after spin annihilation did not lead to significant improvement of the UHF and UMP2 results. In contrast to the ROHF, UHF and UMP2 results, the DF(USVWN, UBVWN, UBLYP) and hybrid HF/DF(UB3LYP) methods, as well as the AM1-HE, gave much better results. The calculated EAad values decreased, as predicted by most of the models, in the order EAad(I) > EAad(VI) > EAad(XI). The differences in the EAs, EAad(I)-EAad(VI) and EAad(I)-EAad(XI), were consistently predicted to be about 8-9 and 17-18 kcal/mol, respectively, by the DF, B3LYP and AM1-HE models. The performance of the PM3 and SAM1 models was not as good as the AM1 model. Of all the methods tested, the B3LYP/6-311G(d,p) model is concluded to give the most accurate quantitative trend (I(42.6) > VI(33.1) > XI(23.7)) in EAad. The predicted trend in EA can satisfactorily be rationalized by the calculated LUMO orbital energies, atomic charges and spin density distributions. Analysis of the spin density data predicts that phenoxyl- and anilino-type radical anions predominate in the p-benzosemiquinones of I and XI, respectively, while both phenoxyl- and anilino-type radicals contribute to the structure of the p-benzosemiquinone of VI, with the anilino-type predominating.

Benzoquinones↗
PubMed1976

Chemical models of oxidative phosphorylation.

Chemical models for coupling oxidation to phosphorylation are summarized and examined both from the standpoint of organic reaction mechanisms and with respect to their relevance to mitochondria and chloroplasts. In order to accelerate the progress of our research in bioenergetics, it is suggested to focus at least as much attention on structural biochemistry as on phenomenological observations of energy-transducing membranes.

Binding Sites↗
PubMed2002

Biomimetic oxidation of 2-methylimidazole derivative with a chemical model system for cytochrome P-450.

A chemical model system for cytochrome P-450, consisting of tetraphenylporphyrin manganese chloride (TPPMnCl) and iodosylbenzene, efficiently oxidized 2-methylimidazole to 2-methylimidazolone. This system was next applied to 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramide, a muscarinic acetylcholine receptor antagonist under clinical trial, affording the previously unisolated imidazole ring 5-mono-oxidized derivative that is considered to be the precursor of the main metabolites. This system, which is superior to the copper-ascorbate system, should be applicable to in vitro studies of various drugs containing the 2-methylimidazole moiety.

Biomimetics↗
PubMed1990

Calculation of site affinity constants and cooperativity coefficients for binding of ligands and/or protons to macromolecules. II. Relationships between chemical model and partition function algorithm.

The relationships between the chemical properties of a system and the partition function algorithm as applied to the description of multiple equilibria in solution are explained. The partition functions ZM, ZA, and ZH are obtained from powers of the binary generating functions Jj = (1 + kappa j gamma j,i[Y])i tau j, where i tau j = p tau j, q tau j, or r tau j represent the maximum number of sites in sites in class j, for Y = M, A, or H, respectively. Each term of the generating function can be considered an element (ij) of a vector Jj and each power of the cooperativity factor gamma ij,i can be considered an element of a diagonal cooperativity matrix gamma j. The vectors Jj are combined in tensor product matrices L tau = (J1) [J2]...[Jj]..., thus representing different receptor-ligand combinations. The partition functions are obtained by summing elements of the tensor matrices. The relationship of the partition functions with the total chemical amounts TM, TA, and TH has been found. The aim is to describe the total chemical amounts TM, TA, and TH as functions of the site affinity constants kappa j and cooperativity coefficients bj. The total amounts are calculated from the sum of elements of tensor matrices Ll. Each set of indices (pj..., qj..., rj...) represents one element of a tensor matrix L tau and defines each term of the summation. Each term corresponds to the concentration of a chemical microspecies. The distinction between microspecies MpjAqjHrj with ligands bound on specific sites and macrospecies MpAqHR corresponding to a chemical stoichiometric composition is shown. The translation of the properties of chemical model schemes into the algorithms for the generation of partition functions is illustrated with reference to a series of examples of gradually increasing complexity. The equilibria examined concern: (1) a unique class of sites; (2) the protonation of a base with two classes of sites; (3) the simultaneous binding of ligand A and proton H to a macromolecule or receptor M with four classes of sites; and (4) the binding to a macromolecule M of ligand A which is in turn a receptor for proton H. With reference to a specific example, it is shown how a computer program for least-squares refinement of variables kappa j and bj can be organized. The chemical model from the free components M, A, and H to the saturated macrospecies MpAQHR, with possible complex macrospecies MpAq and AHR, is defined first.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMedDate not supplied

Chemical models for the lethality curves of toxic metal ions.

Several equilibrium models are presented for the calculation of the lethality curves due to toxic metal ions. In the first, a generalized Langmuir model is used to examine the occupancy of linear arrays of 1, 2, ..., 6 interacting adsorption sites on a macromolecular species. This model permits one to take into account cooperative or anticooperative interaction of occupied adjacent sites. In the second model, a variety of nonlinear distributions of interacting sites (in triangular, square, tetrahedral, and octahedral array) are analyzed, and the corresponding adsorption isotherms are calculated. The third model treated, the Ising model, represents a linear infinite array of sites with nearest-neighbor interactions. The fourth and fifth models examined are the Bragg-Williams model and the quasi-chemical model, both of which permit approximate treatment of infinite arrays of adsorption sites having arbitrary numbers of interacting nearest neighbors. These models are then combined with the assumption that the differential distribution of mortality is a known function of the fraction of sites occupied by the toxic metal ion to generate lethality curves. Results are computed for the special case in which the differential mortality distribution is Gaussian, and it is shown that all of the models are capable of generating lethality curves of the sort found experimentally when plots are made of percentage lethality versus log dosage. The models can also be used for situations in which toxic effects other than lethality arise from the interaction of a toxic molecule or ion with more than one site on a linear macromolecule or for reactions involving certain other arrays of specified configuration.

Binding Sites↗
PubMed1985

Photosynthetic water oxidation. A new chemical model.

A sequential four-step chemical model for the water oxidation process in photosystem II is presented, based on the observation that a peroxide-linked biquinone complex can be chemically formed as a result of hydroxide ion addition to quinone. In our model, the hydroxide ion intermediate is generated in photosystem II as a result of proton abstraction from water. In the model, the first two flashes of light raise the oxidation state of the bimanganese center, while the third and fourth flashes of light sequentially generate the peroxide-linked biquinone which is then directly oxidized by the bimanganese center to produce oxygen and regenerate quinone.

Benzoquinones↗
PubMed1992

Chemical models of epilepsy with some reference to their applicability in the development of anticonvulsants.

This paper reviews chemical models of epilepsy and their relevance in the identification and characterization of anticonvulsants. For each convulsant we discuss possible modes of administration, clinical type(s) of seizures induced, proposed mechanism(s) of epileptogenesis and, where available, responsiveness of the induced seizures to anticonvulsants. The following compounds are reviewed: pentylenetetrazol, bicuculline, penicillin, picrotoxin, beta-carbolines, 3-mercaptopropionic acid, hydrazides, allylglycine; the glycine antagonist strychnine; gamma-hydroxybutyrate; excitatory amino acids (glutamate, aspartate, N-methyl-D-aspartate, quisqualate, kainate, quinolinic acid); monosubstituted guanidino compounds, metals (alumina, cobalt, zinc, iron); neuropeptides (opioid peptides, corticotropin releasing factor, somatostatin, vasopressin); cholinergic agents (acetylcholine, acetylcholinesterase inhibitors, pilocarpine); tetanus toxin; flurothyl; folates; homocysteine and colchicine. Although there are a multitude of chemical models of epilepsy, only a limited number are applied in the routine screening of potential anticonvulsants. Some chemical models have a predictive value with regard to the clinical profile of efficacy of the tested anticonvulsants. Some chemical models may contribute to a better understanding of possible mechanisms of epileptogenesis.

Animals↗
PubMed1987

Aflatoxin B1 activation to a plasmid mutagen by a chemical model of cytochrome P-450.

Aflatoxin B1 (AFB1) was oxidised by a chemical model of cytochrome P-450 and the products obtained analysed by reversed-phase hplc. The oxidation system employs a water-insoluble iron(III)porphyrin catalyst (tetraphenylporphinatoiron(III) chloride; FeTPPCl) and an oxygen donor, iodosylbenzene (PhIO). The two AFB1 products obtained from this reaction were derived by initial oxidation across the 8-9 double bond of AFB1 and subsequent breakdown of AFB1-8,9-epoxide, the compound postulated to be the ultimate carcinogenic and mutagenic derivative of AFB1. Oxidation of AFB1 by the porphyrin-catalysed system in the presence of calf-thymus DNA, resulted in the formation of AFB1-DNA adducts identical to those formed in vivo and in vitro after liver mono-oxygenase activation. The chemical model system was therefore used on a microscale to react AFB1 with plasmid pHR1800, a plasmid containing the genes for beta-lactamase (amp-r) and galactokinase (galK). AFB1-modified plasmid DNA was then transformed into E. coli AB1886 (uvrA-) and the effects of the AFB1-DNA adducts on plasmid survival and the ability of pHR1800-transformed bacteria to metabolise galactose, were then studied. The results showed an AFB1 dose-dependent decrease in plasmid survival and increase in the mutation frequency of the galK gene only when the complete oxidation system was used to generate the reactive AFB1 metabolite.

Aflatoxin B1↗
PubMed2005

Chemical models of genetic toggle switches.

We study by mean-field analysis and stochastic simulations chemical models for genetic toggle switches formed from pairs of genes that mutually repress each other. To determine the stability of the genetic switches, we make a connection with reactive flux theory and transition state theory. The switch stability is characterized by a well-defined lifetime tau. We find that tau grows exponentially with the mean number N of transcription factor molecules involved in the switching. In the regime accessible to direct numerical simulations, the growth law is well-characterized by tau approximately N(alpha) exp(bN), where alpha and b are parameters. The switch stability is decreased by phenomena that increase the noise in gene expression, such as the production of multiple copies of a protein from a single mRNA transcript (shot noise) and fluctuations in the number of proteins produced per transcript. However, robustness against biochemical noise can be drastically enhanced by arranging the transcription factor binding domains on the DNA such that competing transcription factors mutually exclude each other on the DNA. We also elucidate the origin of the enhanced stability of the exclusive switch with respect to that of the general switch; while the kinetic prefactor is roughly the same for both switches, the "barrier" for flipping the switch is significantly higher for the exclusive switch than that for the general switch.

Animals↗