Oligomers-model building in protonation equilibria of sitagliptin

Mixed protonation constants of sitagliptin phosphate at various ionic strengths I (mol kg^?1) in range 0.01 and 0.50 and at 298.15 K are determined using FBSTAC4 and HYPERQUAD nonlinear regression analyses of the potentiometric titration curve. At a low concentration c _L = 1.1 mmol kg^?1 the monomers L, LH, LH₂, LH₃ and LH₄ dominate, while for a concentration range from c _L = 13.7 to 24.7 mmol kg^?1 dimers L₂H₂, L₂H₃, L₂H₄ and L₂H are mainly present. The regression programme has almost no influence on the precision of the protonation constants. The accuracy of the protonation constants log β _qr depends on the accuracy of the group parameters. As two group parameters c _L,0, c _H,T are ill-conditioned in a model, their determination is therefore uncertain: both can significantly cause a systematic error in the estimated common parameters log₁₀β _qr . Fitness tests using regression diagnostics have proven the reliability of the parameter estimates.      

Quantitative treatments of protonation equilibria shifts in micellar systems.

The paper reviews the theoretical models and equations used for the interpretation of weak acid dissociation equilibria in the presence of micellar systems. The models and the equations of the literature can be rewritten and reinterpreted in terms of the generalized pseudophase model, for which the basic equations are reported. Some new relationships for the titration of weak acids in micellar systems are presented.     

The deprotonation and protonation equilibria of a hypericin derivative in aqueous solution

Summary A hypericin derivative ,'-appended at the methyl groups with two polyethylene glycol moieties (about 23 units long) and capped with acetyl groups was synthesized starting from emodin. This derivative proved to be soluble in water and was investigated by means of spectrophotometric titrations and electrophoresis experiments. Deprotonation at thebay-region hydroxyl group was observed atpK _a=1.6. This was followed by a second deprotonation step of aperi-hydroxyl group at apK _a value of 9.4. This derivative could be protonated at the carbonyl group characterized by apK _a value of –5.7. FrompK _a determinations in water-ethanol mixtures the correspondingpK _a values of hypericin itself determined in such mixtures were extrapolated to the aqueous phase. This resulted in estimatedpK _a values of 1.8, 9.2, and –6.

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Deprotonierungs- und Protonierungsgleichgewichte eines Hypericinderivates in wäßriger Lösung

Zusammenfassung Ein an den Methylgruppen von Hypericin mit endständig acetylierten Polyethylenglykolketten (ungefähr 23 Einheiten lang) ,'-disubstituiertes Derivat wurde ausgehend von Emodin synthetisiert. Dieses Derivat ist wasserlöslich, und es wurde mit Hilfe von spektrophotometrischen Titrationen und Elektrophorese untersucht. Die Deprotonierung derbay-Hydroxylgruppe erfolgt beipK _a=1.6. Diese wird von einem zweiten Deprotonierungsschritt an einerperi-Hydroxylgruppe bei einempK _a-Wert von 9.4 gefolgt. Dieses Derivat konnte an der Carbonylgruppe protoniert werden, was durch einenpK _a-Wert von –5.7 charakterisiert ist. Ausgehend vonpK _a-Messungen in Wasser-Ethanol-Mischungen wurden die entsprechendenpK _a-Werte auch für das Hypericin selbst in wäßriger Phase extrapoliert. Dies führte zu geschätztenpK _a-Werten von 1.8, 9.2 und –6.

     

On the protonation equilibria of sephadex C-25 and C-50

The system H(+)Na(+) has been studied on Sephadex C-25 and C-50 at two ionic strengths by potentiometry. The data have been fitted by the H?gfeldt three-parameter model. For ionic strength 0.100 M (Na)ClO(4) an excellent fit is obtained with a standard deviation of +/-0.013 for both gels. For ionic strength 0.010 M (Na)ClO(4) a satisfactory fit could only be obtained by excluding the lowest and highest pH-value for each gel.     

Addressing selectivity criteria in binding equilibria

Chemical systems, in particular those involving biological and environmental backgrounds, develop through selective processes which are determined by multiple equilibria. Several methods that have been developed to assess thermodynamic selectivity in binding equilibria, including the analysis of selectivity coefficients, the use of calculated species distribution diagrams, selectivity diagrams, and conditional stability constants, are reviewed in this paper with reference to examples mainly related to chemical systems of biological and/or environmental concern. Also the concept of binding affinity has been dealt with, since binding selectivity in equilibrium systems relates to the different affinities with which chemical species bind to each other.     

Gel speciation studies-II An extension of earlier studies of the protonation equilibria of cross-linked carboxymethyldextran

The potentiometric properties of the rigidly cross-linked Sephadex gel CM-25 have been studied. The gel was equilibrated in sodium perchlorate at fixed concentration levels (0.010 and 0.0010M) and with variable concentration levels of NaClO(4) (from 0.0010 to 0.10M). The volume of the gel was measured for every equilibrated sample simultaneously with the solution pH and pNa. The pK computed after correction for a Donnan potential term was found to be independent of alpha, the degree of neutralization, and ionic strength; its value of 3.35 +/-0.15 was in excellent agreement with the intrinsic pK measured earlier for the flexible CM-50 Sephadex gel and reported for its linear polyelectrolyte analogue, carboxymethyldextran. An interesting observation from these studies is the efficient screening of the charged surface by the counter-ions in the presence of a three-dimensional charged network.     

Multiple isomers and protonation sites of the phenylalanine/serine dimer

Our investigation of the phenylalanine/serine (Phe/Ser) protonated dimer suggests that the intermolecular interaction between the two amino acids is more complex than could have been anticipated from previous studies of similar systems. Isomer-specific infrared (IR) spectra, recorded at an internal temperature of ~10 K, demonstrate the presence of at least five isomers with nonzwitterionic structures. Moreover, isotopic substitution experiments provide evidence for different protonation sites among these isomers.     

A study on protonation equilibria in a series of amino-1-(substituted phenyl)pyrazoles

The ionization constants (proton gain) of 3-,4-, and 5-amino-1-(substituted phenyl)pyrazoles, have been measured in 10% v/v ethanol-water. pKa values show a good linear dependence on Hammett substituent constants. The reaction constants Q are in keeping with the respective protonation sites in the three series of monocations. The uv spectra of 1-(m-nitrophenyl)pyrazole and 1-(p-methoxyphenyl)pyrazole and of their 3-amino, 4-amino, 5-amino analogues recorded in acidic and neutral media, show that in the three series the first protonation site does not change with change in substituent at phenyl ring.     

Dendrimers as size selective inhibitors to protein-protein binding

This communication describes how the "quantized" size effect of dendrimers can be exploited towards a size selective binding mechanism for the inhibition of protein-protein binding.     

Robust identification of binding hot spots using continuum electrostatics: application to hen egg-white lysozyme

Binding hot spots, protein regions with high binding affinity, can be identified by using X-ray crystallography or NMR spectroscopy to screen libraries of small organic molecules that tend to cluster at such hot spots. FTMap, a direct computational analogue of the experimental screening approaches, uses 16 different probe molecules for global sampling of the surface of a target protein on a dense grid and evaluates the energy of interaction using an empirical energy function that includes a continuum electrostatic term. Energy evaluation is based on the fast Fourier transform correlation approach, which allows for the sampling of billions of probe positions. The grid sampling is followed by off-grid minimization that uses a more detailed energy expression with a continuum electrostatics term. FTMap identifies the hot spots as consensus clusters formed by overlapping clusters of several probes. The hot spots are ranked on the basis of the number of probe clusters, which predicts their binding propensity. We applied FTMap to nine structures of hen egg-white lysozyme (HEWL), whose hot spots have been extensively studied by both experimental and computational methods. FTMap found the primary hot spot in site C of all nine structures, in spite of conformational differences. In addition, secondary hot spots in sites B and D that are known to be important for the binding of polysaccharide substrates were found. The predicted probe-protein interactions agree well with those seen in the complexes of HEWL with various ligands and also agree with an NMR-based study of HEWL in aqueous solutions of eight organic solvents. We argue that FTMap provides more complete information on the HEWL binding site than previous computational methods and yields fewer false-positive binding locations than the X-ray structures of HEWL from crystals soaked in organic solvents.     

Metal ligation regulates conformational equilibria and binding properties of cavitands

A self-folding cavitand binds quinuclidinium cation in its vase conformation and lanthanum ions in its kite conformation. Metal coordination provides a novel switching mechanism for the uptake and release of guests.     

Direct observation of the protonation state of an imino sugar glycosidase inhibitor upon binding

Glycosidases are some of the most ubiquitous enzyme in nature. Their biological significance, coupled to their enormous catalytic prowess derived from tight binding of the transition state, is reflected in their importance as therapeutic targets. Many glycosidase inhibitors are known. Imino sugars are often potent inhibitors, yet many facets of their mode of action, such as their degree, if any, of transition-state "mimicry" and their protonation state when bound to the target glycosidase remain unclear. Atomic resolution analysis of the endoglucanase, Cel5A, in complex with a cellobio-derived isofagomine in conjunction with the pH dependence of Ki and kcat/KM reveals that this compound binds as a protonated sugar. Surprisingly, both the enzymatic nucleophile and the acid/base are unprotonated in the complex.     

Role of short-range electrostatics in torsional potentials

A force field needs to decide if it should contain a torsional potential or not. A helpful guide to this decision should come from a quantum mechanical energy partitioning. Here we analyze the energy profiles of eight simple molecules (ethane, hydrogen peroxide, hydrazine, methanol, acetaldehyde, formamide, acetamide and N-methylacetamide) subject to rotation around a torsion angle. Coulomb interaction energies between all atom pairs in a molecule are monitored during the rotation. Atoms are defined as finite electron density fragments by quantum chemical topology, a method that enables well-defined short-range interactions (1-2, 1-3 and 1-4). Energy profiles of Coulomb interaction energies mostly counteract the ab initio energy profiles. This and future work strives to settle ambiguities in current force field design.     

Spectrometric study of tautomeric and protonation equilibria of o-vanillin Schiff base derivatives and their complexes with Cu(II)

Electronic absorption and emission properties of a series of Schiff bases derived from 2-hydroxy-3-methoxybenzaldehyde and 2-aminopyridine, 2,3-diaminopyridine, 2,6-diaminopyridine, or 3-aminomethylpyridine were studied in solvents of different polarities. The interconversion of the enolimine to the ketoamine tautomeric form was observed for compound 1, 6-methoxy-2-(3-pyridylmethyliminomethyl)phenol, and the corresponding equilibrium constant was estimated in several solvents. Protonation constants of all the investigated compounds were determined spectrophotometrically in the methanol/water 1/4 system. The effect of copper(II) ions on absorption and on the emission spectra of these ligands was examined in the buffered dioxane/water 1/1 system (pH 5.8). Strong complexation of Cu(II) and formation of a 1:1 complex were observed for the bis-Schiff base derived from 2,3-diaminopyridine. The complex of copper(II) with compound 1 was isolated and characterized by elemental analysis, magnetic susceptibility measurement, UV-vis and IR spectrometry.     

Boundary conditions in local electrostatics algorithms

We study the simulation of charged systems in the presence of general boundary conditions in a local Monte Carlo algorithm based on a constrained electric field. We first show how to implement constant-potential, Dirichlet boundary conditions by introducing extra Monte Carlo moves to the algorithm. Second, we show the interest of the algorithm for studying systems which require anisotropic electrostatic boundary conditions for simulating planar geometries such as membranes.