Significant discrepancies between van't Hoff and calorimetric enthalpies.

Naghibi, Hossein; Tamura, Atsuo; Sturtevant, Julian M.

doi:10.1073/pnas.92.12.5597

Cited by 281 publications

(217 citation statements)

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“…This figure is 3.5% less than the average value at 25 "C in Table 2 Table 1 by amounts well beyond experimental uncertainty, with the ratio AH,,//AH,,H varying from 1.21 at 7 "C to 1.09 at 40 "C, and that AHVH varies with temperature with AC,, (vH) = 8.1 cal K-' mol-'. As noted in our earlier paper (Naghibi et al, 1995), we have yet to find a set of data for which AC,, (vH) as evaluated from the equilibrium data is zero within experimental uncertainty. In other words, we have not yet found a system for which the usual procedure of linear least squaring of In K versus 1/ T is appropriate.…”

Section: Calorimetric Enthalpiesmentioning

confidence: 85%

“…In a recent paper (Naghibi et al, 1995), we pointed out the frequent occurrence of discrepancies between van't Hoff enthalpies derived from the temperature variation of equilibrium constants and enthalpies determined by direct calorimetric measurements. To date we have not found a single case where there is agreement, to within experimental uncertainty, between these two types of enthalpy values.…”

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confidence: 99%

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Significant discrepancies between van't hoff and calorimetric enthalpies. II

1995

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Isothermal calorimetric titration of 18-crown-6 ether with BaClz in pure aqueous solution over the temperature range 7-40 "C gives precise binding constants and enthalpy changes. Nonlinear least-squares fitting of the binding constants to the integrated van't Hoff equation, including a temperature-independent change in heat capacity, leads to van't Hoff enthalpies that differ significantly from the observed calorimetric enthalpies. This perplexing discrepancy appears at present to be very widely occurring. Keywords: calorimetric enthalpies; calorimetry; temperature variation of equilibrium constants; van't Hoff enthalpiesIn a recent paper (Naghibi et al., 1995), we pointed out the frequent occurrence of discrepancies between van't Hoff enthalpies derived from the temperature variation of equilibrium constants and enthalpies determined by direct calorimetric measurements. To date we have not found a single case where there is agreement, to within experimental uncertainty, between these two types of enthalpy values. All the systems but two considered in our earlier paper involved proteins, the two exceptions being the binding of cyclohexanol to a-and 0-cyclodextrins. Even in these cases involving relatively simple molecules, there were significant differences between van't Hoff and calorimetric enthalpies. Izatt et al. (1976) and Briggner and Wadso (1991) published calorimetric data on the binding of barium chloride to 18-crown-6 ether, the latter publication including equilibrium data at three temperatures. This system would appear to be an excellent system for further study of the problem concerning van't Hoff and calorimetric enthalpies because of its simplicity:18-crown-6 is a solid cyclic polyether of 264 Da molecular mass; both reactants are readily available in very pure form; and they can be weighed and dissolved in pure water for the reaction. Izatt et al. reported data at 25 "C only, and Briggner and Wadso limited their study to three temperatures. Because our method for analyzing such data requires measurements at four or more temperatures, we have undertaken further study of this system.

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Section: Calorimetric Enthalpiesmentioning

confidence: 85%

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confidence: 99%

Significant discrepancies between van't hoff and calorimetric enthalpies. II

1995

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“…Early studies of the thermodynamics of processes involving proteins were, in general, usually carried out by examining the temperature-dependence of the dissociation constant (van't Hoff analysis). These studies are notoriously prone to errors of types that would give the appearance of EEC (Liu & Sturtevant, 1995, 1997Naghibi et al 1995). The development of isothermal titration calorimetry (ITC) has, however, largely removed these errors, but EEC has not disappeared.…”

Section: Enthalpy/entropy Compensation (Eec)mentioning

confidence: 99%

Designing ligands to bind proteins

Whitesides

Krishnamurthy

2005

Quart. Rev. Biophys.

123

108

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The ability to design drugs (so-called 'rational drug design') has been one of the long-term objectives of chemistry for 50 years. It is an exceptionally difficult problem, and many of its parts lie outside the expertise of chemistry. The much more limited problem -how to design tight-binding ligands (rational ligand design) -would seem to be one that chemistry could solve, but has also proved remarkably recalcitrant. The question is 'Why is it so difficult?' and the answer is 'We still don't entirely know'. This perspective discusses some of the technical issues -potential functions, protein plasticity, enthalpy/entropy compensation, and others -that contribute, and suggests areas where fundamental understanding of protein-ligand interactions falls short of what is needed. It surveys recent technological developments (in particular, isothermal titration calorimetry) that will, hopefully, make now the time for serious progress in this area. It concludes with the calorimetric examination of the association of a series of systematically varied ligands with a model protein. The counterintuitive thermodynamic results observed serve to illustrate that, even in relatively simple systems, understanding protein-ligand association is challenging. Rational ligand designMolecular recognition is, in a sense, the most important process in molecular biology. Most of the reactions and interactions that dominate the operation of living systems -recognition of sequences in nucleic acids by complementary nucleic acids and by proteins; folding of proteins; recognition of ligands by proteins; interaction of drugs and target proteins; differential stabilization of the transition state and ground state of biochemical reactions by enzymes; many others -involve molecular recognition. Understanding molecular recognition is centrally important to understanding -and controlling -the set of molecular processes that make up the cell, and life.The problem of understanding molecular recognition translates, in utilitarian terms, into being able to design ligands that bind to specific sites on biomacromolecules (most often, proteins). This problem is intellectually enormously interesting, since solving it would provide ways of modulating the activities of proteins in vivo. More practically, it is central to the idea of socalled 'rational drug design'. Generating drugs has been, and remains, a difficult, expensive, failure-prone, and highly empirical activity. The difficulty and cost of developing new drugs has become prohibitive for the pharmaceutical industry, and without improved efficiency and productivity from the R&D groups of this industry, there is a widespread concern that the rate at which new drugs will be developed in the future will be substantially less than it has been in the past. The process of generating a drug is, of course, much more complicated than simply designing a ligand that targets a protein: 'hits' and 'leads' are an important part of the process, but ADME/Tox/PK/PD (adsorption, distribution, metabolism, excre...

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“…36, No. 39, 1997 11903 can be calculated from the slope of the van't Hoff plot :In the case of protein p6, the van't Hoff plot is nonlinear, which would correlate with a considerable standard heat capacity change (∆C°p ,obs ) upon complex formation, sinceThe data were analyzed according to the nonlinear integrated van't Hoff equation (Andreu et al, 1983;Naghibi et al, 1995): where the superscripts indicate the corresponding thermodynamic values at a reference temperature (T°). This analysis resulted in a constant negative heat capacity change ∆C°p ,obs ) -0.92 ( 0.14 kcal mol -1 and variable enthalpy values (at 20°C, ∆H°o bs ) -11.3 ( 1.9 kcal mol -1 ).…”

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Phage Ø29 Protein p6 Is in a Monomer−Dimer Equilibrium That Shifts to Higher Association States at the Millimolar Concentrations Found in Vivo

et al. 1997

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Protein p6 from Bacillus subtilis phage Ø29 (M r ) 11 800) binds in Vitro to DNA forming a large nucleoprotein complex in which the DNA wraps a multimeric protein core. The high intracellular abundance of protein p6 together with its ability to bind the whole Ø29 DNA in Vitro strongly suggests that it plays a role in viral genome organization. We have determined by sedimentation equilibrium analysis that protein p6 (1-100 µM range), in the absence of DNA, is in a monomer-dimer equilibrium, with an association constant (K 2 ) of ∼2 × 10 5 M -1 . The intracellular concentration of protein p6 (∼1 mM) was estimated measuring the number of copies per cell (7 × 10 5 ) and the cell volume (1 × 10 -15 L). At concentrations around 1 mM, protein p6 associates into oligomers. This self-association behavior is compatible with a dimer-hexamer model (K 2,6 ) 3.2 × 10 8 M -2 ) or with an isodesmic association of the dimer (K ) 950 M -1 ), because the apparent weight-average molecular mass (M w,a ) does not reach saturation at the highest protein concentrations. The sedimentation coefficients of protein p6 monomer and dimer were 1.4 and 2.0, respectively, compatible with translational frictional ratios (f/f o ) of 1.15 and 1.30, which slightly deviate from the hydrodynamics of a rigid globular protein. Taking together these results and considering the structure of the nucleoprotein complex, we speculate that the observed oligomers of protein p6 could mimic a scaffold on which DNA folds to form the nucleoprotein complex in ViVo.The genomes of prokaryotic organisms are organized in higher order nucleoprotein complexes that, besides a packaging role, mediate fundamental processes of DNA such as replication, transcription, recombination, and transposition (Echols, 1990). Some of these complexes are assembled by architectural elements that by analogy to eukaryotic systems are referred to as histone-like proteins. In Escherichia coli, the major constituents of bacterial nucleoid are the HU heterodimer [reviewed in Drlica and Rouviere-Yaniv (1987)] and H-NS [reviewed in Ussery et al. (1994) and Atlung and Ingmer (1997)]. These proteins are small, very abundant, and bind DNA with little or no sequence specificity, usually through the minor groove. The pleiotropic nature of mutations in their corresponding genes indicates that these proteins have multiple functions. HU is reported to be involved in replication, transposition, and transcriptional control, while H-NS has been suggested to be a modulator of regulated gene expression.Protein p6 from Bacillus subtilis phage Ø29 has some features resembling those expected for a histone-like protein.Protein p6 is the most abundant protein in Ø29-infected cells and binds in Vitro to the viral DNA forming multiple complexes spread virtually throughout the entire genome, of sizes ranging from ∼100 base pairs (bp) up to ∼2 kilobases (kb) (Gutiérrez et al., 1994). Protein p6 binds to DNA through the minor groove, and it does not recognize a specific sequence, but rather a DNA structural f...

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Significant discrepancies between van't Hoff and calorimetric enthalpies.

Cited by 281 publications

References 5 publications

Significant discrepancies between van't hoff and calorimetric enthalpies. II

Significant discrepancies between van't hoff and calorimetric enthalpies. II

Designing ligands to bind proteins

Phage Ø29 Protein p6 Is in a Monomer−Dimer Equilibrium That Shifts to Higher Association States at the Millimolar Concentrations Found in Vivo

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