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PubMed2002

Thermodynamics and kinetics of protein folding: an evolutionary perspective.

This article appeals to an evolutionary model which postulates that primordial proteins were described by small polypeptide chains which (i) lack disulfide bridges, and (ii) display slow folding rates with multi-state kinetics, to determine relations between structural properties of proteins and their folding kinetics. We parameterize the energy landscape of proteins in terms of thermodynamic activation variables. The model studies evolutionary changes in these thermodynamic parameters, and we invoke relations between these activation variables and structural properties of the protein to predict the following correspondence between protein structure and folding kinetics. 1. Proteins with inter- and intra-chain disulfide bridges: large variability in both folding rates and stability of intermediates, multi-state kinetics. 2. Proteins which lack inter and intra-chain disulfide bridges. 2.1 Single-domain chains: fast folding rates; unstable intermediates; two-state kinetics. 2.2 Multi-domain monomers: intermediate rates; metastable intermediates; multi-state kinetics. 2.3 Multi-domain oligomers: slow rates; metastable intermediates; multi-state kinetics. The evolutionary model thus provides a kinetic characterization of one important subfamily of proteins which we describe by the following properties: Folding dynamics of single-domain proteins which lack disulfide bridges are described by two-state kinetics. Folding rate of this class of proteins is positively correlated with the thermodynamic stability of the folded state.

Disulfides↗
PubMed2003

The driving force for life's emergence: kinetic and thermodynamic considerations.

The principles that govern the emergence of life from non-life remain a subject of intense debate. The evolutionary paradigm built up over the last 50 years, that argues that the evolutionary driving force is the Second Law of Thermodynamics, continues to be promoted by some, while severely criticized by others. If the thermodynamic drive toward ever-increasing entropy is not what drives the evolutionary process, then what does? In this paper, we analyse this long-standing question by building on Eigen's "replication first" model for life's emergence, and propose an alternative theoretical framework for understanding life's evolutionary driving force. Its essence is that life is a kinetic phenomenon that derives from the kinetic consequences of autocatalysis operating on specific biopolymeric systems, and this is demonstrably true at all stages of life's evolution--from primal to advanced life forms. Life's unique characteristics--its complexity, energy-gathering metabolic systems, teleonomic character, as well as its abundance and diversity, derive directly from the proposition that from a chemical perspective the replication reaction is an extreme expression of kinetic control, one in which thermodynamic requirements have evolved to play a supporting, rather than a directing, role. The analysis leads us to propose a new sub-division within chemistry--replicative chemistry. A striking consequence of this kinetic approach is that Darwin's principle of natural selection: that living things replicate, and therefore evolve, may be phrased more generally: that certain replicating things can evolve, and may therefore become living. This more general formulation appears to provide a simple conceptual link between animate and inanimate matter.

Animals↗
PubMed1976

Thermodynamic conpensation in microbial thermal death. Studies with yeasts.

Sixty eight Arrhenius plots of thermal death in six mesophilic yeast species, tested at various concentrations of NaC1, lacked an isokinetic temperature. Nevertheless the deltaHnot equal to/deltaSnot equal to plot was apparently linear with a slope corresponding to 314degrees K. It was concluded the linear thermodynamic compensation of thermal death is non-existent in heterogeneous groups of yeasts and is unlikely to occur in hetero-geneous groups of other organisms and that deltaHnot equal to/deltaSnot equal to plots lack sensitivity for the detection of non-linearity over narrow temperature ranges. However, the deltaHnot equal to and deltaSnot equal to parameters of thermal death displayed non-linear compensation in such a way that the extrapolated Arrhenius plots of death attained nearly identical values near the respective maximum temperatures for growth. Linear thermodynamic compensation occurred in each of the six strains, when stationary populations of the same strain were tested at various NaC1 concentrations. On the other hand, exponential populations of each of the strains, tested in the same way, lacked an isokinetic temperature of thermal death. The significance of linear and non-linear thermodynamic compensation in biological rate processes is discussed.

Cell Survival↗
PubMed1983

[Hydrophobic acridine dyes for fluorescence staining of mitochondria in living cells. 1. Thermodynamic and spectroscopic properties of 10-n-alkylacridine orange chlorides].

10-n-Alkyl-acridine-orange-chlorides (alkyl-AOs) are excellent dyes for fluorescence staining of mitochondria in living cells. The thermodynamic and spectroscopic properties of the series alkyl = methyl to nonyl have been investigated. The dyes form dimers in aqueous solution. The dimerisation is mainly a consequence of the hydrophobic interaction. The dissociation constant K respectively association constant K-1 of the dimers describes the hydrophobic interaction and therefore the hydrophobic properties of the dye cations. The dissociation constant K = K0 at the standard temperature T = 298 K has been determined spectroscopically in aqueous solution. It depends on the length of the alkyl residue n-CmH2m + 1 (m = 1 - 9) (Table 2). In addition the standard dissociation enthalpies (energies) delta H0 and dissociation entropies delta S0 have been determined from the temperature dependence of K (Table 2). With increasing chain length m the thermodynamic parameters K0, delta H0, delta S0 decrease. Therefore with growing m the dimers are stabilized. This stabilization is an entropic effect which is diminished by the energetic effect. The change of the thermodynamic parameters with m is in agreement with the concept of hydrophobic interaction and the stabilization of water structure in the surroundings of hydrophobic residues. As one would expect nonyl-AO is the most hydrophobic dye of the series. As an example the spectroscopic properties of nonyl-AO have been determined. We measured the absorption, luminescence and polarization spectra in rigid ethanol at 77 K. Under these conditions alkyl-AOs associate like dyes in Water at room temperature. The spectra depend on the concentration of the solution. In very dilute solution we observe mainly the spectra of the monomers M, in concentrated solution the spectra of the dimers D. The spectra of M and D are characteristically different. The monomers have one long wave length absorption M1 = 20.000 cm-1 with resonance fluorescence. In addition there is a long living phosphorescence at 16.600 cm-1. Its polarization is nearly perpendicular to the plane of the AO residue. The dimers have two long wave length absorption bands D1 = 18.700 and D2 = 21.200 cm-1 with very different intensities. D1 has very low intensity and is forbitten, D2 is allowed. D1 shows fluorescence. Phosphorescence has not been observed. D1, D2 and also M1 are polarized in the plane of the AO residue. At short wave length absorption and polarization spectra are very similar. From the spectra we constructed the energy level diagram of M and D (Fig. 9). The first excited state of M splits in D in two levels. The level splitting and the transition i

Acridine Orange↗
PubMed1982

The significance of changes in thermodynamic affinity induced by aldosterone in sodium-transporting epithelia.

The energetics of sodium transport were examined in toad (and occasionally frog) skin, with particular emphasis on the effect of aldosterone. Thermodynamic affinity was computed according to Essig and Caplan. Following treatment with antidiuretic hormone or drugs believed to affect only the apical membrane barrier, no change in thermodynamic affinity was observed either acutely (after one to two hours) or chronically (after 18-odd hours hours). By contrast, following treatment with aldosterone overnight, thermodynamic affinity was considerably increased, whether or not incubation was conducted in the presence of sodium in the outer solution; addition of glucose at the end of incubation, whereby sodium transport was stimulated further, failed to influence affinity as measured. The stoichiometry between sodium transport and oxygen consumption was, however, unchanged by aldosterone treatment in short-circuit conditions, neither was that fraction of aerobic metabolism unrelated to sodium transport influenced. It is concluded that the change observed with aldosterone can be directly ascribed to the hormone, as it is independent of glucose availability and of sodium transport. Aldosterone action, at least following prolonged incubation, therefore does not involve only an increase in apical conductance for sodium.

Aldosterone↗
PubMed1979

Surface thermodynamics of leukocyte and platelet adhesion to polymer surfaces.

Adhesion of leukocytes and platelets to solid substrates of different surface tensions and hence different wettability is studied from a thermodynamic point of view. A simple thermodynamic model predicts that a cellular adhesion should increase with increasing surface tension of the solid substrate if the surface tension of the medium in which the cells are suspended is lower than the surface tension of the cells. If the surface tension of the suspending medium is higher than that of the cells, the opposite behavior is predicted. These predictions are borne out completely by neutrophil adhesion tests, where the surface tension of the aqueous suspending medium is varied by addition of dimethyl sulfoxide (DMSO). Platelet adhesion experiments also confirm these predictions, the only difference being that surface tensions of the suspending medium above that of the platelets cannot be realized, owing to exudation of surface active solutes from the platelets. Utilization of the thermodynamic prediction that cellular adhesion should become independent of the surface tension of the substrate when the surface tensions of the cells and that of the suspending medium are equal leads to a value of the surface tension of neutrophils of 69.0 erg/cm(2), in excellent agreement with the value obtained from contact angles measured on layers of cells.

Cell Adhesion↗
PubMed1988

Thermodynamic aspects of cell spreading on solid substrata.

To verify the validity of thermodynamic approaches to the prediction of cellular behavior, cell spreading of three different cell types on solid substrata was determined in vitro. Solid substrata as well as cell types were selected on the basis of their surface free energies, calculated from contact angle measurements. The surface free energies of the solid substrata ranged from 18-116 erg cm-2. To measure contact angles on cells, a technique was developed in which a multilayer of cells was deposited on a filter and air dried. Cell surface free energies ranged from 60 erg cm-2 for fibroblasts, and 57 for smooth muscle cells, to 91 for HeLa epithelial cells. After adsorption of serum proteins, cell surface free energies of all three cell types converged to approx 74 erg cm-2. The spreading of these cell types from RPMI 1640 medium on the various solid substrata showed that both in the presence and in the absence of serum proteins in the medium, cells spread poorly on low energy substrata (Ys less than 50 erg cm-2), whereas good cell spreading was observed on the higher energy substrata. Calculations of the interfacial free energy of adhesion (delta Fadh) show that delta Fadh decreases with increasing Ys, and equals zero around 45 erg cm-2 for all three cell types in the presence of serum proteins and for HeLa epithelium cells in the absence of serum proteins. This explains the spreading of these cells on the various substrata upon a thermodynamic basis. The results clearly show that substratum surface free energy has a predictive value with respect to cell spreading in vitro, both in the presence and absence of serum proteins. It is noted, however, that interfacial thermodynamics fail to explain the behavior of fibroblasts and smooth muscle cells in the absence of serum proteins, most likely because of the relatively high surface charges of these two cell types.

Adsorption↗
PubMed2004

An equilibrium thermodynamic model of the sequestration of calcium phosphate by casein phosphopeptides.

Sequestration of calcium phosphate by caseins occurs in the Golgi region of mammary secretory cells during lactation, where it helps to prevent calcification of the gland and to deliver high concentrations of calcium and phosphate to the neonate in the form of milk. Calcium phosphate nanoclusters are formed when a core of amorphous calcium phosphate is sequestered within a shell of casein or casein phosphopeptides. The nanoclusters can form spontaneously from a supersaturated solution or by dispersion of a precipitate of calcium phosphate, demonstrating that they are thermodynamically stable complexes. The average size and chemical composition of the complexes are largely independent of the solution conditions (pH, temperature, peptide concentration, salt composition and rate of reaction) under which they form. Larger, metastable, colloidal particles can form if there is not enough of the phosphopeptide to sequester all the calcium phosphate, or, transiently, if the salt and peptide solutions are mixed together without sufficient care. A thermodynamic model of the sequestration process is presented which makes use of an invariant ion activity product observed in nanocluster-containing solutions. In any given solution that has thermodynamic stability, the extent of the sequestration reaction can be calculated from the empirical formula of the nanoclusters using the criterion that the solution should have the equilibrium value of the invariant ion activity product. Other members of the paralogous group of secretory calcium-binding phosphoproteins to which caseins belong may also be able to sequester calcium phosphate in biological fluids such as saliva and in the extracellular matrix of mineralizing tissues.

Animals↗
PubMed2002

Thermodynamic activation properties of elongation factor 2 (EF-2) proteins from psychrotolerant and thermophilic Archaea.

In this study, the thermodynamic activation parameters of cold-adapted proteins from Archaeaa are described for the first time for the irreversible protein unfolding and ribosome-dependent GTPase activity of elongation factor 2 (EF-2) from the psychrotolerant Methanococcoides burtonii and the thermophilic Methanosarcina thermophila. Thermolability of Methanococcoides burtonii EF-2 was demonstrated by a low activation free-energy of unfolding as a result of low activation-enthalpy. Although structural data for EF-2 are presently limited to protein homology modeling, the observed thermodynamic properties are consistent with a low number of noncovvalent bonds or an altered solvent interaction, causing a loss of entropy during the unfolding process. A physiological concentration of potassium aspartate or potassium glutamate was shown to stabilize both proteins against irreversible denaturation by strengthening noncovalent interactions, as indicated by increased activation enthalpies. The transition state of GTPase activity for Methanococcoides burtonii EF-2 was characterized by a lower activation enthalpy than for Methanosarcina thermophila EF-2. The relative entropy changes could be explained by differential displacement of water molecules during catalysis, resulting in similar activation free energies for both proteins. The presence of solutes was shown to facilitate the breaking of enthalpy-driven interactions and structuring of more water molecules during the reaction. By studying the thermodynamic activation parameters of both GTPase activity and unfolding and examining the effects of intracellular solutes and partner proteins (ribosomes), we were able to identify enthalpic and entropic properties that have evolved in the archaeal EF-2 proteins to enable Methanococcoides burtonii and Methanosarcina thermophila to adapt to their respective thermal environments.

Archaeal Proteins↗
PubMed1984

The thermodynamics of flavin binding to the apoflavodoxin from Azotobacter vinelandii.

A thermodynamic study of the binding of flavins (FMN, FAD, 8-carboxylic acid-riboflavin) to the purified apoflavodoxin from Azotobacter vinelandii has been conducted. The binding of FMN was studied at a number of temperatures (10, 15, 20, 25, and 30 degrees C), pH's (6.0, 7.4, and 9.0), and buffer conditions. The binding of FAD was studied at pH 7.4 and 25 degrees C under a number of buffer conditions. The binding of 8-carboxylic acid-riboflavin to the apoflavodoxin and the binding of FMN to the dimeric form of the apoflavodoxin were investigated at pH 7.4 and 25 degrees C. Enthalpies of binding for FMN, FAD, and 8-carboxylic- acid-riboflavin were -28.3, -16.6, and -14.0 kcal mol-1, respectively. The enthalpy of binding of FMN to the dimeric form of the apoflavodoxin was -22.2 kcal mol of binding sites-1. Binding constants of about 10(8), 10(6), and 10(6) were obtained for the binding of FMN, FAD, and 8-carboxylic acid-riboflavin, respectively. Using established thermodynamic relationships free energy and entropy changes were calculated. The entropy data indicate that a large degree of ordering of the system occurs upon flavin binding. The pH data suggest that FMN may bind in both the mono- and dianion forms, and that binding doesn't change the pKa of any functional group in the system. It appears that the phosphate group is probably responsible for approximately half the binding enthalpy observed for the binding of FMN. The temperature-dependence data over the temperature range studied is biphasic, centered at 20 degrees C, indicating that flavin binding occurs to the protein in two thermodynamic states corresponding to the two heat capacities observed. These findings are used to discuss a model for flavin binding.

Apoproteins↗
PubMed1985

The thermodynamics of bovine and porcine insulin and proinsulin association determined by concentration difference spectroscopy.

Difference spectroscopy was used to determine the equilibrium constants and thermodynamic parameters for the monomer-dimer association of bovine and porcine insulin and bovine proinsulin at pH 2.0 and 7.0. At pH 2 delta G degree 25, delta S degree, and delta H degree for dimerization of bovine insulin were found to be -6.6 kcal/mol, -18 cal/mol-deg, and -12 kcal/mol, respectively. Porcine insulin behaved similarly to bovine insulin in its dimerization properties in that delta G degree 25, delta S degree, and delta H degree were found to be -6.8 kcal/mol, -14 cal/mol-deg, and -11 kcal/mol, respectively. At pH 7 delta G degree 25, delta S degree, and delta H degree for dimerization of bovine insulin were found to be -7.2 kcal/mol, -16 cal/mol/deg, and -12 kcal/mol, respectively. At pH 7.0 delta G degree 25, delta S degree, and delta H degree for dimerization of porcine insulin were -6.7 kcal/mol, -11.6 cal/mol-deg, and -10 kcal/mol, respectively. The similarity in the thermodynamic parameters of both insulin species at the different pH's suggests that there are minimal structural changes at the monomer-monomer contact site over this pH range. The dimerization of both insulin species is under enthalpic control. This may suggest that the formation of the insulin dimer is not driven by hydrophobic bonding but, rather, is driven by the formation between subunits of four hydrogen bonds in an apolar environment. At pH 2 delta G degree 25, delta S degree, and delta H degree for dimerization of bovine proinsulin were found to be -5.3 kcal/mol, -26 cal/mol-deg, and -13 kcal/mol, respectively. At pH 7 delta G degree 25, delta S degree, and delta H degree for dimerization of proinsulin were -5.9 kcal/mol, -4.2 cal/mol-deg, and -7.2 kcal/mol, respectively. Although the presence of the C-peptide on proinsulin does not drastically affect the overall free energy change of dimer formation (as compared to insulin), the other thermodynamic parameters are rather drastically altered. This may be because of electrostatic interactions of groups on the C-peptide with groups on the B-chain which are near the subunit contact site in the insulin dimer.

Animals↗
PubMed1985

Effect of thermodynamic nonideality on the subcellular distribution of enzymes: adsorption of aldolase to muscle myofibrils.

An expression is derived whereby allowance may be made for the effects of thermodynamic nonideality on the biphasic interaction of a macromolecular solute with an immobilized reactant. This quantitative description, written in terms of activity coefficients expressed as virial coefficients on the basis of excluded volume, also takes into account the space-filling effect of an inert macromolecule present in the reaction mixture. Advantage is then taken of the theory to consider the effect of bovine serum albumin on the interaction of aldolase with bovine cardiac muscle myofibrils in I 0.158 imidazole-chloride buffer, pH 6.8. Partition equilibrium studies are used to establish that inclusion of a moderate concentration (14 mg/ml) of serum albumin in reaction mixtures leads to a 35-40% increase in the apparent binding constant written in terms of reactant molarities, and that the enhancement is attributable entirely to nonideality inasmuch as the same thermodynamic binding constant pertains. This investigation of thermodynamic nonideality arising from the space-filling effects of inert macromolecules on enzyme partition reinforces the possibility that some enzymes may be distributed between soluble and adsorbed states in the highly concentrated macromolecular environment of the cell cytoplasm.

Adsorption↗
PubMed1988

Thermodynamic bookkeeping when nucleotides bind. Applications of the theory of linked functions.

The thermodynamic theory of linked functions was used to determine the numbers of modifier ions involved when nucleotides dissociate. Nucleotide dissociation constants, obtained spectrophotometrically using Dowex-1 resin as a model system, were plotted on log/log paper with respect to the modifier concentrations. The slopes of the lines represent the net number of modifier molecules/ions involved in the dissociation. Varying numbers of nucleotides are bound to the resin because the resin capacity is determined by the total number of charges bound. The nucleotides bind to the resin at comparable diffusion-limited rates, irrespective of how tightly they bind. When ATP binds at pH 6.8, 4 chlorides, 4 formates, 2 succinates or 1.4 citrates are displaced, indicating that the fully charged (ATP4-) nucleotide binds. By comparing ATP, ADP and AMP it was possible to evaluate the contributions of the adenosine moiety and each phosphate to the binding. Between pH 2 and 3, where ATP has two negative charges, ATP binds largely as the trianion, displacing 2.7 chlorides and 0.7 protons. In the presence of 4 mM magnesium, 0.58 magnesiums facilitate the dissociation by chelating 58% of the liberated ATP. Calcium behaved similarly to magnesium but aluminum, at pH 6.8, promoted the binding of ATP as an (A1.ATP)3- complex with the concomitant liberation of three chloride ions. These experimental thermodynamic stoichiometries were found to be independent of the concentrations of the other modifiers present. Thermodynamic linkage stoichiometries can be evaluated from log K vs. log (modifier) plots when a direct determination of modifier binding is impossible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1988

The thermodynamic essence of the reversible inactivation of Na+/K+-transporting ATPase by various digitalis derivatives is relaxation of enzyme conformational energy.

This paper reports on the kinetic and thermodynamic parameters describing the interaction of selected digitalis derivatives with hog and guinea-pig cardiac (Na+ + K+)-ATPase (Na+/K+-transporting ATPase EC 3.6.1.37). 32 digitalis derivatives were characterized as to the values of the delta G0', delta G----not equal to, and delta G----not equal to quantities in their interaction with (Na+ + K+)-ATPase from hog cardiac muscle in the presence of ATP, Mg2+, Na+ and K+. Nine derivatives were additionally characterized as to the values of the delta H0', delta S0', delta H----not equal to, delta S----not equal to, delta H not equal to, and delta S not equal to quantities in their interaction with the hog enzyme promoted by ATP, Mg2+ and Na+ in the presence or absence of K+. The formation of the inhibitory complexes is in any case an endothermic, entropically driven process. The Gibbs energy barriers in the formation and dissociation of the complexes, delta G----not equal to and delta G----not equal to, are imposed by large, unfavourable delta H not equal to values. K+ decreases the delta G0' value by increasing the delta G----not equal to value more than the delta G----not equal to value. In comparison with hog (Na+ + K+)-ATPase, the interaction of three derivatives with guinea-pig cardiac enzyme in the presence of ATP, Mg2+, Na+ and K+ is characterized by lower delta G0' values caused by lower favourable delta S0' values, and is accompanied by lower delta G----not equal to values. The magnitude of the kinetic parameters and the characteristic of the thermodynamic quantities describing the interaction between various digitalis derivatives and (Na+ + K+)-ATPase, indicate the induction of substantial conformational changes in the enzyme protein. A large entropy gain in the enzyme protein, observed irrespective of enzyme origin and ligation, appears to be the common denominator of the inhibitory action of all digitalis derivatives studied, suggesting that the digitalis-elicited relaxation of high conformational energy (negentropy strain) of the enzyme protein is the thermodynamic essence of the reversible inactivation of (Na+ + K+)-ATPase.

Adenosine Triphosphate↗
PubMed1980

Evaluation of enzyme systems and their regulation: the inapplicability of irreversible thermodynamics.

The formalism called irreversible thermodynamics has been examined for its applicability to the description of enzymic reactions. The basic assumption of this formalism is that the net flux through a reaction is related to the free energy change, a relationship which is usually assumed to be linear. These assumptions are shown to be approximately true for the trivial case of an enzyme reaction within 0.8 kJ/mol (0.2 kcal/mol) of equilibrium in the absence of changes in any regulatory parameters (such as inhibitor, activator, or enzyme concentration). For all other reaction conditions the net flux is not related to the free energy change and in special cases for which an apparent relationship is seen, it is not linear. Thus, application of the formalism of irreversible thermodynamics gives rise to qualitatively and quantitatively erroneous results and conclusions. Since most regulatory enzymic reactions are far from equilibrium, and the net reaction rate of such reactions is regulated by changes in inhibitors, activators and/or enzyme concentration, the formalism of irreversible thermodynamics is in general neither applicable nor useful in understanding the behavior of biological reaction systems.

Allosteric Regulation↗
PubMed1978

Thermodynamic studies of the interaction of alpha-chymotrypsin with water. II. Statistical analyses of the enthalpy-entropy compensation effect.

Differential enthalpies (deltaH) and entropies (deltaS) of the interaction of water with a high and low temperature conformer of alpha-chymotrypsin were determined previously by multitemperature sorption measurements. The changes in (deltaH) and (deltaS) with water content of the protein were found to show a pronounced compensation pattern. It is known that van 't Hoff data may exhibit enthalpy-entropy compensation, which is entirely due to statistical error propagation. To discriminate between artifactual and significant compensation, the experimental results are analyzed by statistical methods. The results of two different statistical analyses show that a linear, chemically caused compensation effect can be established for the interaction of water with both chymotrypsin conformers. The compensation temperature beta = deltaH/deltaS was found to be 433 +/- 22 K. The compensation effect is detectable only in the water content range above the monolayer volume (upsilonm), computed by the Brunauer, Emmett and Teller equation. This result is discussed in terms of a monolayer hydration mechanism, formulated on the basis of previous thermodynamic results: The interaction of the first water monolayer with the charged and polar surface area of the dry protein, largely stabilizes its tertiary structure. Further water addition then occurs to a practically invariable protein surface. According to this mechanism (which ensures a maximum of conformational stability with a minimum of hydration water), large conformational changes can be expected to occur mainly in the monolayer water content range. This expectation is confirmed by extra-thermodynamic data (infrared and X-ray measurements). The thermodynamic quantities of the sorption process are thus governed by conformational effects below upsilonm. Above the monolayer water content range, however, the water binding process per se strongly predominates. The deltaH/deltaS compensation effect established for this water content range, is thus attributable to phase transitions of water molecules from the gas (or liquid) phase to the protein-bound state (or vice versa). A possible relationship between the linear compensation effect established in this study, and the compensation phenomenon observed in reactions in aqueous solution is discussed.

Calorimetry↗
PubMed1992

Biochemical and thermodynamic aspects of the binding of [3H]glycine to its strychnine-insensitive recognition site associated with the N-methyl-D-aspartate receptor complex.

The molecular mechanism of interaction between glycine and its strychnine-insensitive binding site linked to the N-methyl-D-aspartate receptor was investigated by examining on the one hand the thermodynamic properties of glycine binding, and, on the other hand, the effects of various functional group modifying agents on ligand binding. Raising the incubation temperature from 0 degrees to 37 degrees resulted in a consistent decrease of glycine binding affinity. Calculation of thermodynamic parameters from the corresponding Van't Hoff plot showed that the binding of glycine was mainly entropy-driven, the change in enthalpy contributing only little (25-30%) to the change in Gibbs free energy. Chemical modification with the sulfhydryl-directed agents p-hydroxy-mercuribenzoate and N-ethyl-maleimide showed free -SH groups to be critical for ligand binding to the receptor site. Furthermore, guanidino groups on arginyl residues, sensitive to 2,3-butanedione, were also found to participate in glycine binding. Both the -SH and the guanidino groups could be protected against their inactivation by co-incubation with glycine, indicating a direct involvement of these functional groups in the binding process. Dithiothreitol, a disulfide-reducing agent, likewise prevented [3H]glycine binding, suggesting that the glycine recognition site is stabilized by at least one disulfide bridge. It is concluded that the binding of glycine probably involves a strong ion-ion interaction between its carboxyl group and a positively charged guanidino group at the receptor site, resulting in a thermodynamically favorable increase in entropy by displacement of water molecules from the latter and a concomitant decrease in enthalpy. Furthermore, at least one free sulfhydryl group seems to participate in the binding process.

Animals↗
PubMed1995

Binding thermodynamics of adenosine A2a receptor ligands.

The thermodynamic parameters delta G degree, delta H degree, and delta S degree of the binding equilibrium of seven adenosine agonists and five xanthine antagonists binding specifically to adenosine A2a receptors were determined by means of affinity measurements at six different temperatures (0, 10, 20, 25, 30 and 35 degrees) and van't Hoff plots. Affinity constants were measured on rat striatum membranes by saturation experiments for the selective A2a agonist 2-[p-(carboxy-ethyl)-phenethylamino-]5'-(N-ethyl)carboxamidoadenos ine ([3H]CGS 21680) and by inhibition assays of [3H]CGS 21680 binding for all other compounds. Scatchard plots were monophasic in the full range of temperatures, indicating a single class of high affinity binding sites whose receptor density, BMAX, is essentially temperature independent. Van't Hoff plots were linear in the temperature range 0-30 degrees for agonists and 0-35 degrees for antagonists; their thermodynamic parameters fall, respectively, in the ranges 7 < or = delta H degree < or = 50 kJ/mol and 177 < or = delta S degree < or = 278 J K-1 mol-1 and -36 < or = delta H degree < or = -7 kJ/mol and -33 < or = delta S degree < or = 94 J K-1 mol-1, showing that agonist binding is entropy-driven while antagonist binding is enthalpy-driven. The results are compared with those already reported for the binding of the same compounds to rat brain minus striatum adenosine A1 receptors obtained by displacing [3H]CHA as A1 selective radioligand (Borea PA et al., Mol Neuropharmacol 2: 273-281, 1992). The comparison suggests that the two receptors are very similar as far as their binding sites are concerned and possibly philogenetically related. The analysis of thermodynamical data makes it possible to propose an analogical model of drug-receptor interaction which may account for both affinity and intrinsic activity properties.

1-Methyl-3-isobutylxanthine↗