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At least 19 recordsLinked to original sources
PubMed1979

Calculation of the concentrations of free cations and cation-ligand complexes in solutions containing multiple divalent cations and ligands.

The method described permits the computation of the concentrations of free ions and ion-ligand complexes in a solution containing arbitrary numbers of divalent cations and ligands. It is required that the pH be known, along with appropriate sets of ligand-hydrogen and ligand-divalent cation concentration binding constants. It is assumed that these sets of constants are chosen to be consistent with the ionic strength of the complete solution which contains the divalent cations and ligands. The technique is an iterative one which provides upper and lower bounds for the values of the unknowns. The method does not require initial guesses at the values of the unknowns, and it gives correct answers even when the concentrations involved are many orders of magnitude apart. The present formulation of the problem is restricted to the case where only one cation can bind to a given ligand at any one time. The method is applicable to large molecules with multiple "sub-ligands" provided these sub-ligands are independent in their function as ion-binding sites. These sub-ligands need not all have the same properties. It is also shown that a simple modification of the method permits the determination of the subset of total ion concentrations that are required in order to produce a specified subset of free ion concentrations. The modifications required to include monovalent cation binding are presented in outline form.

Adenosine Triphosphate↗
PubMed1978

Comparison of the interaction of mono- and oligovalent ligands with cholera toxin. Demonstration of aggregate formation at low ligand concentrations.

The stimulation by cholera toxin of adenylate cyclase in Chinese hamster ovarian cells could be inhibited by various ligands. The latter have been shown to contain the structural oligosaccharide entities required for binding to cholera toxin, established as Galbeta1 leads to 3GalNAcbeta1 leads to 4Gal3 comes from 2alphaNeuAc. The different inhibitory potency of the ligands thereby correlates with the size of the aggregates formed with the toxin, which in turn depends on the valency of the ligands. The conclusion is drawn from a comparison of the interaction of cholera toxin and its B-protomer with ganglioside II3NeuAc-GgOse4-Cer, the newly synthesized bis-(monosialo-gangliotetraityl)amine and monosialogangliotetraose. In a double diffusion test cholera toxin B-protomer precipitated with the ganglioside II3 NeuAcGgOSE4-Cer and the divalent ligand bis(monosialo-gangliotetraityl)amine, suggesting the formation of high molecular weight aggregates, whereas no precipitation was observed with the monovalent monosialo-gangliotetraose. By ultracentrifugation analysis, aggregate formation of the cholera toxin B-protomer could be demonstrated with the ganglioside II3 NeuAc-GgOse4-Cer and bis(monosialo-gangliotetraityl)amine at a concentration at which the ganglioside was assumed to be monodisperse. Ganglioside/cholera toxin B-protomer complexes sediment faster than those of the toxin and bis(monosialo-gangliotetraityl)amine, suggesting higher aggregation of cholera toxin B-protomer with the former. On the other hand, no sedimentation with monosialo-gangliotetraose was observed. By equilibrium displacement dialysis, however, a comparable high affinity of binding to cholera toxin B-protomer of both the mono- and divalent oligosaccharides was demonstrated. Furthermore, values for the maximal concentration of the bound ligand from these binding experiments with cholera toxin B-protomer established molar ratios of ligand to protein of 4 to 1 and 2 to 1 for monosialo-gangliotetraose and bis(monosialo-gangliotetraityl)amine, respectively. From the results it is concluded that the lipophilic moiety of the ganglioside is not directly involved in the binding process to the toxin protein but leads to an oligovalency of this ligand, due to formation of micellar or submicellar structures.

Adenylyl Cyclases↗
PubMed1978

Cooperative and non-cooperative binding of large ligands to a finite one-dimensional lattice. A model for ligand-oligonucleotide interactions.

A combinatorial approach is employed to calculate exact expressions for the extent of binding to a finite one dimensional lattice of ligands which cover more than one lattice site. The binding may be either cooperative or non-cooperative. It is found that the assumption of an effectively infinite lattice is generally a good one, except with relatively low concentrations of strongly cooperative ligands. An approach to analyzing experimental data is suggested which makes explicit use of the lattice length dependence of binding to extract more information about the binding parameters than can be obtained using the infinite lattice approximation. It is shown that irreversible binding cannot be viewed as a limiting case of reversible binding. The reasons for this difference are discussed, and expressions for the extent of irreversible binding are derived.

Binding Sites↗
PubMed1978

Selenium protection against mercury toxicity: high binding affinity of methylmercury by selenium-containing ligands in comparison with sulfur-containing ligands.

In determining the protection of selenium against mercury toxicity, the binding affinity of methylmercury by various selenium-containing ligands was investigated by proton magnetic resonance (PMR) spectroscopy. The most striking feature was the small J199Hg-1H value of the selenocysteamine- and selenocysteine-methylmercury complexes, namely, the high affinity of the selenohydryl group to the mercury in comparison with those of the sulfhydryl and amino groups. The order of binding affinity of the coordination groups toward methylmercury is clearly SeH greater than SH greater than or equal to Se-Se greater than NH2 greater than S-S, SeCH3, SCH3. A definite correlation was found to exist between the mercury-proton coupling constants and the chemical shifts of methyl groups of the methylmercury complexes. A relationship between the order (Se greater than S greater than NH2) of affinity for methylmercury and the basicity (or electronegativity and covalent radius) of the donor groups was also discussed. These results suggest the high covalency of the CH3Hg-Se bond, which involves dpi-dpi back bonding.

Chemical Phenomena↗
PubMed1975

Correlation between quaternary structure and ligand dissociation kinetics for fully liganded hemoglobin.

The quaternary structures of fully liganded adult hemoglobin and hemoglobin Kansas (alpha2beta2 102 Asn-thr) bound by carbon monoxide or nitric oxide were spectroscopically characterized using high-resolution nuclear magnetic resonance (NMR) and ultraviolet circular dichroism (CD). The spectral markers used for the quarternary transition were the line in the NMR spectrum in H2O-14 ppm downfield from 2,2-dimethyl-2-silapentane-5-sulfonate and the negative peak at 285 nm in the ultraviolet CD spectrum. In the nitrosyl derivatives, these two structural markers were compared with the electron paramagnetic resonance (EPR) spectrum at room temperature for the purpose of correlating structural changes in the protein with changes at the heme...

Binding Sites↗
PubMed1975

Oxygen binding by hemocyanin from Levantina hierosolima. II. Interpretation of cooperativity in terms of ligand-ligand linkage.

Oxygen binding by hemocyanin from Levantina hierosolima was studied at pH 7.30, in solutions containing calcium in the concentration range 0-1 M. The binding was found to be cooperative, the degree of cooperativity being calcium concentration dependent. The dependence on calcium concentration of the affinity toward oxygen for both deoxygenated and oxygenated hemocyanin was interpreted in terms of two oxygen-linked calcium ions, one promoting and the other opposing oxygen binding. The results show that cooperativity may be fully explained on the basis of a coupling of the free energy of binding between calcium and oxygen.

Animals↗
PubMed1979

Ligand competition curves as a diagnostic tool for delineating the nature of site-site interactions: theory.

A few molecular models have been developed in recent years to explain the mechanism of cooperative ligand binding. The concerted model of Monod, Wyman and Changeux and the sequential model of Koshland, Némethy and Filmer were formulated to account for positively cooperative binding. The pre-existent asymmetry model and the sequential model can account for negatively cooperative ligand binding. In most cases, however, it is virtually impossible to deduce the molecular mechanism of ligand binding solely from the shape of the binding isotherm. In the present study we suggest a new strategy for delineating the molecular mechanism responsible for cooperative ligand binding from binding isotherms. In this approach one examines the effect of one ligand on the cooperativity observed in the binding of another ligand, where the two ligands compete for the same set of binding sites. It is demonstrated that the cooperativity of ligand binding can be modulated when a competitive ligand is present in the protein-ligand binding mixture. A general mathematical formulation of this modulation is presented in thermodynamic terms, using model-independent parameters. The relation between the Hill coefficient at 50% ligand saturation with respect to ligand X in the absence, h(x), and in the presence of a competing ligand Z, h(x,z), is expressed in terms of the thermodynamic parameters characterizing the binding of the two ligands. Then the relationship between h(x) and h(x,z), in terms of the molecular parameters of the different allosteric models, is explored. This analysis reveals that the different allosteric models predict different relationships between h(x,z) and h(x). These differences are especially focused when Z binds non-cooperatively. Thus, it becomes possible, on the basis of ligand binding experiments alone, to decide which of the allosteric models best fits a set of experimental data.

Binding Sites↗
PubMed1978

Functional consequences of ligand-dependent conformational changes in trypsin-solubilized and in membrane particle constrained-acetylcholinesterase.

The effect of a class of ligands on the catalytic activity of acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) from Torpedo californica electroplax tissue has been studied via the transient reaction of a fluorophoric acetylcholine analog, 7-(N,N-dimethyl)carbamoxy-N-methylquinolinium iodide (M7C). These "peripheral" ligands inhibit the formation of a metastable carbamyl-enzyme intermediate from M7C. They induce slow isomerization to a new conformational state that shows little or no reaction with M7C. At saturating ligand concentration, the unimolecular isomerization rate constant is 0.03 +/- 0.01 sec-1, a slow rate compared to the rate of carbamylation of the active conformation. Peripheral ligands alter the distribution between reactive and unreactive conformations, thus inducing biphasic rates and amplitudes of carbamylation. The amplitudes, but not the two specific rates, are affected by the concentration of ligand. Zn2+ and d-tubocurarine are two ligands that induce the same slow isomerization rate. On the basis of this identity of function by ligands of disparate structure, we postulate the existence of only a single active conformation and a single inactive conformation (stabilized by interaction with both ligands). In the absence of ligands, the active conformation predominates. Peripheral ligands bind specifically to the inactive conformation. Alkaline earth cations such as Ca2+ and Mg2+ interact strongly and preferentially with the active conformation and drive the conformational equilibrium toward the active state. Ligand-induced inactivation is observed both with highly purified trypsin-solubilized enzyme and with enzyme bound to unfractionated membrane fragments.

Acetylcholine↗
PubMed1979

Transient intermediates in the reduction of Fe(III) myoglobin-ligand complexes by electrons at low temperature.

1. The reductions of a number of sperm-whale Fe(III) myoglobin-ligand complexes by electrons generated by gamma-irradiation in ethylene glycol/water glass, have been investigated by using low-temperature spectrophotometry. The ligands are azide, fluoride, imidazole and water. 2. The reduction of the Fe(III) myoglobin-ligand complexes at 77 K leads to the formation of low-spin liganded Fe(II) myoglobin, in the case of the azide, imidazole and water derivatives, while the reduction of the fluoride derivative proceeds both by a pathway involving prior dissociation of the ligand and with the ligand in position. 3. Investigation of the effect of temperature on the stability of the Fe(II) myoglobin-ligand complexes indicates that more than one bound states exists in dissociation of the ligand molecule from the ferrous heme iron of the reduced azide and imidazole derivatives. 4. The results are discussed in terms of the possible structure of the Fe(II) myoglobin complexes and it is suggested that the low-spin state is created by a strained configuration of the heme center with the iron atom in an intermediate position relative to the heme plane.

Animals↗
PubMed1975

Interaction of effecting ligands with lac repressor and repressor-operator complex.

The equilibrium association constants for the binding of a wide variety of effecting ligands of the lac repressor were measured by equilibrium dialysis. Also, detailed investigations of the apparent rate of dissociation of repressor-operator comples as a function of ligand concentration were carried out for several inducers and anti-inducers. The affinity of repressor-ligand comples for operator DNA was evaluated from the specific rate constants at saturating concentrations of effecting ligand. By fitting the experimental data depicting the functional dependence of the rate of dissociation upon ligand concentrations to calculated curves, assuming simple models of the induction mechanism, the equilibrium association constant for the binding of effecting ligand to repressor-operator comples was determined. Inducers reduce the affinity of lac repressor for operator DNA by a factor of approximately 1000 under standard conditions; the extent of destabilization depends on Mg2+ ion concentration. Anti-inducers increase the affinity of repressor for operator at most a factor of five. Only one neutral ligand, which binds to repressor without altering the stability of repressor-operator comples, was found. No homotropic or heterotropic interactions in the binding of effecting ligands either to repressor or to repressor-operator complex are evident.

Binding Sites↗
PubMedDate not supplied

[Precise relationships for calculating the binding of regulatory proteins and other lattice ligands in double-stranded polynucleotides].

The binding of long multisite ligands to double-stranded nucleic acids is considered. The ligand is taken as a lattice of AT- and GC-specific reaction centres the sequence of which is complementary to the base pair sequence in the specific ligand interaction site on DNA. Exact equations are derived for the two cases: that when a ligand binds in a fixed orientation relative to the DNA and that when it can be attached to DNA in the two alternative orientations related by two-fold rotation. Included in the formulation are two alternative orientations related by two-fold rotation. Included in the formulation are the ligand size effects as well as cooperative effects for which the interactions between the nearest neighbour adsorbed molecules are responsible. In particular, if cooperative interactions are allowed only between the adjacent ligand molecules related by two-fold rotation symmetry, the ligands would tend to associate into symmetrical "dimers" upon binding to DNA. This model enables one to explain the recognition of specific base sequences which are related by two-fold rotation symmetry and are complementary to the sequence of ligand reaction centres. Numerical calculations are carried out for several specific cases and for various values of parameters involved in the theoretical model.

Chemical Phenomena↗
PubMed2025

An image-based protein-ligand binding representation learning framework via multi-level flexible dynamics trajectory pre-training.

MOTIVATION: Accurate prediction of protein-ligand binding (PLB) relationships plays a crucial role in drug discovery, which helps identify drugs that modulate the activity of specific targets. Traditional biological assays for measuring PLB relationships are time consuming and costly. In addition, models for predicting PLB relationships have been developed and widely used in drug discovery tasks. However, learning more accurate PLB representations is essential to meet the stringent standards required for drug discovery. RESULTS: We propose an image-based PLB representation learning framework, called ImagePLB, which equips ligand representation learner (LRL) and protein representation learner (PRL) to accept 3D multi-view ligand images and protein graphs as input, respectively, and learns rich interaction information between ligand and protein through a binding representation learner (BRL). Considering the scarcity of protein-ligand pairs, we further propose a multi-level next trajectory prediction (MLNTP) task to pre-train ImagePLB on the 4D flexible dynamics trajectory of 16 972 complexes, including ligand level, protein level, and complex level, to learn information related to trajectories. Besides, by introducing trajectory regularization (TR), we effectively alleviate the problem of high (even almost identical) feature similarity caused by adjacent trajectories. Compared with the current state-of-the-art methods, ImagePLB has achieved competitive improvements on PLB-related prediction tasks, including protein-ligand affinity and efficacy prediction tasks. This study opens the door to the image-based PLB learning paradigm. AVAILABILITY AND IMPLEMENTATION: All data and implementation details of code can be obtained from https://github.com/HongxinXiang/ImagePLB.

Ligands↗
PubMed1975

Resonance Raman scattering from hemoproteins. Effects of ligands upon the Raman spectra of various C-type cytochromes.

Resonance Raman spectra were measured for various C-type cytochromes (mammalian cytochrome c, bacterial cytochrome c3, algal photosynthetic cytochrome f, and alkylated cytochrome c) and a B-type cytochrome (cytochrome b5) in their reduced and oxidized states. (1) For ferrous alkylated cytochrome c, a Raman line sensitive to the replacement of an axial ligand of the heme iron uas found around 1540 cm=1. This ligand-sensitive Raman line indicated the transition from acidic (1545 cm-1) to alkaline (1533 cm-1) forms with pK 7.9. The pH dependence of the Raman spectrum corresponded well to that of the optical absorption spectra. (2) For ferrous cytochrome f, the ligand-sensitive Raman line was found at the same frequency as cytochrome c (1545 cm-1). Accordingly two axial ligands are likely to be histidine and methionine as in cytochrome c. (3) For ferrous cytochrome c3, the frequency of the ligand-sensitive Raman line was between those of cytochrome c and cytochrome b5. Since two axial ligands of the heme iron in cytochrome c3 might be histidines. However, a combination of histidine and methionine as a possible set of two axial ligands was not completely excluded for one or two of the four hemes. (4) In ferrous cytochrome b5, two weak Raman lines appeared at 1302 and 1338 cm-1 instead of the strongest band at 1313 cm-1 of C-type ferrous cytochromes. This suggests the practical use of these bands for the identification of types of cytochromes. The difference in frequency and intensity between B- and C-types of hemes implies that the low effective symmetry of the heme in ferrous cytochrome c is due to vibrational coupling of ring modes with peripheral substituents rather than geometrical disortion of heme.

Alkylation↗
PubMed1975

Ligand binding properties of hemoglobin 3 of the trout, Salmo gairdneri. The occurrence of an acid Bohr effect in the absence of heme-heme interaction.

The four components of hemoglobin from the rainbow trout (Salmo gairdneri) have been isolated. The oxygen affinities of the first two components eluted from the DEAE-cellulose column have much smaller pH dependencies than the last two components. These components have very low O2 affinities at low pH. The effect of pH on the equilibrium and kinetics of ligand binding to the third fraction, the pH-dependent component present in greatest amounts, has been studied. Measurements of ligand binding equilibria demonstrate the presence of both an alkaline and an acid Bohr effect. In the region of the alkaline Bohr effect the value of n in the Hill equation is a function of ligand affinity. For CO binding n decreases as the pH is decreased until at pH 6, the minimum ligand affinity is reached. At this pH there is also a complete loss of cooperative ligand binding. Decreasing the pH further results in an increase of ligand affinity, but this acid Bohr effect is not associated with a reappearance of cooperativity. This suggests that Fraction 3 of S. gairdneri is frozen in the low affinity, deoxygenated conformation at low pH and that the quaternary structure does not change even when fully liganded. However, the properties of the low affinity conformation of this hemoglobin are pH-dependent.

Animals↗
PubMed2026

Identification of MHC Ligands Through Allele-Guided Isolation Combined With Machine Learning for Improved MHC Assignment Using ARDisplay-I.

The isolation of major histocompatibility complex (MHC) ligands and subsequent analysis by mass spectrometry is considered the gold standard for defining targets for T cell-based immunotherapies. However, as many targets of high tumor specificity are only presented at low abundance on the cell surface of tumor cells, the efficient isolation of these peptides is crucial for their successful detection. Here, we demonstrate how optimizing the MHC ligand isolation strategy, based on both the presenting MHC alleles and the individual peptide level, enhances the identification of specific MHC ligands. This ideally acknowledges not only the hydrophobicity but also the post-translational modifications of the respective MHC ligands. To further improve the identification and characterization of MHC ligands, we developed an MHC class I ligand prediction algorithm (ARDisplay-I) that outperforms current state-of-the-art tools when benchmarked against competitors such as netMHCpan 4.1, MixMHCpred, or MHCflurry. Implementing these strategies can augment the development of T cell receptor-based therapies by improving the identification of novel immunotherapy targets and enriching the resources available in the computational immunology field through a superior MHC presentation prediction algorithm.

Ligands↗