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PubMedDate not supplied

DNA replication fidelity: kinetics and thermodynamics.

Mechanisms that control the fidelity of DNA replication are discussed. Data are reviewed for 3 steps in a fidelity pathway: nucleotide insertion, exonucleolytic proofreading, and extension from matched and mismatched 3'-primer termini. Fidelity mechanisms that involve predominantly Km discrimination, Vmax discrimination, or a combination of the two are analyzed in the context of a simple model for fidelity. Each fidelity step is divided into 2 components, thermodynamic and kinetic. The thermodynamic component, which relates to free-energy differences between right and wrong base pairs, is associated with a Km discrimination mechanism for polymerase. The kinetic component, which represents the enzyme's ability to select bases for insertion and excision to achieve fidelity greater than that available from base pairing free-energy differences, is associated with a Vmax discrimination mechanism for polymerase. Currently available fidelity data for nucleotide insertion and primer extension in the absence of proofreading appears to have relatively large Km and small Vmax components. An important complication can arise when analyzing data from polymerases containing an associated 3'-exonuclease activity. In the presence of proofreading, a Vmax discrimination mechanism is likely to occur, but this may be the result of two Km discrimination mechanisms acting serially, one for nucleotide insertion and the other for excision. Possible relationships between base pairing free energy differences measured in aqueous solution and those defined within the polymerase active cleft are considered in the context of the enzyme's ability to exclude water, at least partially, from the vicinity of its active site.

DNA Replication↗
PubMed1995

Ultrasonic approach to obtaining partial thermodynamic characteristics of solutions.

We describe a method for evaluating the thermodynamic characteristics both of pure liquids and of solutes in solutions using data derived from ultrasonic velocity measurements. The principal possibility of using ultrasound velocity lies in the fact that the velocity of ultrasound is a simple function of the adiabatic compressibility. The problem is formulated as an initial value problem for the parabolic type differential equations in partial derivatives. The validity of the method is demonstrated by calculation of the thermodynamic parameters for water, glycine and alanine in aqueous solutions at infinite dilution.

Alanine↗
PubMed1994

Thermodynamics of protein folding: effects of hydration and electrostatic interactions.

DNA base sequences contain a variety of information, and this information flows from DNA to a protein through the steps of transcription and translation. The one dimensional information given from DNA is the amino acid sequence of the protein. In an organism, a nascent chain synthesized in vivo from the N-terminus according to the information in DNA folds spontaneously to a native conformation under a given environmental condition, i.e., water is the solvent and concentration of salts, pH, temperature, and pressure are appropriate. The polypeptide chain synthesized chemically from the C-terminus also folds to the native conformation, and often exhibits the proper enzymic activity. X-ray crystallography reveals the three dimensional structure of a protein in crystal, indicating that the location of the constituent atoms in the space is specific for that protein, i.e., the information on how to fold is contained in the amino acid sequence. In order to understand the folding, however, other factors such as geometrical information on each amino acid should be taken into account, because a sequence is one dimensional information and a 3D structure is three dimensional. Environmental conditions are also crucial factors in the folding, since a change in conditions can destroy the native structure. The folding and unfolding phenomena are described in terms of thermodynamics when the processes occur reversibly. As experiments show, the stability of a protein conformation can be described by the free energy of folding or unfolding. Folding of a nascent chain to the native conformation, thus, is interpreted as the process towards a minimum of the folding free energy. Thermodynamic quantities of folding or unfolding are expressed as functions of temperature, pressure, and concentration of reagents such as salts, and the quantities are measured as the differences between states, e.g., the N and D states. Since the effects of surrounding media must be included, the phenomenon in aqueous solution at a given condition of pH and salt concentration is divided into the several steps shown in Fig. 12. The chain molecule has two states, N and D, in vacuo; the molecule is then transferred into water, accompanied by the hydration in both states; next, the ionization process produces electrostatic interactions in the molecule; and finally, addition of chemical reagents like denaturants has other effects on the stability.

Animals↗
PubMed1991

Thermodynamics of phospholipase A2-ligand interactions.

Future investigations into the role of the structure of phospholipid substrates and the interrelationships between substrate, calcium, and enzyme conformation in the activation process are clearly needed. Enzyme dimerization in the activation of phospholipase A2 has been indicated, and a complex equilibrium between calcium, substrate, and monomer and dimer enzyme apparently exists. The incorporation of proton binding further complicates the scheme, and one is quickly faced with obtaining a large number of equilibrium constants in order to describe the system explicitly. Nevertheless, similarly complex systems have been well characterized using thermodynamic approaches such as those described herein. An excellent example is the complex equilibrium involving the protonation of the histidine residues and the binding of a mononucleotide to ribonuclease A. Achieving a complete thermodynamic description of that system allowed the investigators to make strong mechanistic statements about models for the catalytic mechanism of ribonuclease A. Since phospholipase A2 is available for study at the same level of detail, one can anticipate a similar degree of quantitative detail regarding the important interactions of this enzyme to be forthcoming.

Animals↗
PubMed1995

Tight binding affinities determined from thermodynamic linkage to protons by titration calorimetry.

A general titration calorimetry method is described that can be used to determine the affinity of tight binding interactions with proteins. The method is based on the thermodynamic linkage between ligand binding and coupled protonation reactions. The protons linked to a given ligand-binding reaction are measured by titration calorimetry, and integration of the resulting data set yields the pH dependence of the binding affinity based on thermodynamic relationships developed elsewhere. When the pH dependence of the binding affinity is combined with the absolute affinity determined independently at a pH at which the affinity can be conveniently measured, the absolute binding affinity over the entire pH range is determined. The method is well suited for determining high-affinity binding interactions of protein antigens with antibodies, but is applicable to any macromolecular ligand-binding reaction that is coupled to protonation.

Antigen-Antibody Reactions↗
PubMed1996

Kinetics and thermodynamics studies on the interaction of D-amino acid oxidase and sodium n-dodecyl sulphate in the presence and absence of flavin adenine dinucleotide.

The kinetics and thermodynamics of denaturation of D-amino acid oxidase by sodium n-dodecyl sulphate (SDS) was studied in the presence and absence of additional amounts of flavin adenine dinucleotide (FAD) at various temperatures (310-325 K) in 0.02 M sodium pyrophosphate at pH = 8.3. The activity measurement data was gathered with thermodynamic data for further interpretation. The corresponding data shows higher stability for DAO against temperatures and potent denaturants like SDS.

D-Amino-Acid Oxidase↗
PubMed1986

Adsorption thermodynamics of carbofuran on antimony (V) silicate cation exchanger.

The adsorption thermodynamics of carbofuran has been studied on antimony (V) silicate cation exchanger at 30 and 50 degrees C. The adsorption isotherms of carbofuran have been found to follow the Freundlich adsorption model and yield "S" class isotherms. The order of adsorption of carbofuran is in accordance with the partial molal free-energy changes in the exchanger. The thermodynamic equilibrium constant (K0), standard free energy (delta G degrees), enthalpy (delta H degrees), and entropy (delta S degrees) changes have also been calculated for predicting the nature of adsorption.

Adsorption↗
PubMed1990

Thermodynamic properties of globular proteins and the principle of stabilization of their native structure.

A semi-empirical method has been used to estimate the thermodynamic parameters of hydration of buried surface areas of ribonuclease S, lysozyme and myoglobin from the model of complete unfolding according to Ooi et al. ((1987) Proc. Natl. Acad. Sci. USA 84, 3086-3090). The buried surface area of proteins is considered as the difference between the accessible surface area of native protein and the completely extended polypeptide chain according to Lee and Richards ((1971) J. Mol. Biol. 55, 379-400). The contributions of nonpolar and polar protein groups to the general value of Gibbs energy, enthalpy, entropy and heat capacity of hydration have been determined. The obtained results on the thermodynamic behavior of proteins in the process of complete unfolding are in good agreement with the results of microcalorimetric studies of thermal denaturation.

Animals↗
PubMed1995

Thermodynamic aspects of the CO-binding reaction to cytochrome P-450cam. Relevance with their biological significance and structure.

The CO-binding kinetics of cytochrome P-450cam(+) and P-450cam(-) have been measured in the millisecond time domain using a flash photolysis method. We have determined the reaction coordinates for free energy, enthalpy and entropy from the temperature dependence of the overall rate constants of the bimolecular forward (on) and backward (off) reactions. Comparing the thermodynamic profiles of P-450cam with that of myoglobin (Mb) reported so far, the enthalpy and the entropy coordinates exhibit the following remarkable characteristics. The CO-binding equilibrium: The stability of the CO-complex is perfectly entropy-driven for P-450cam, while enthalpy-driven for Mb. This entropy-driven feature for P-450cam is enhanced by the dissociating d-camphor. The on and off activation processes: The on and off reactions for P-450cam are dominantly controlled by the enthalpy and entropy terms, respectively, while those for Mb are rather the reverse of the case of P-450cam. The dissociation of d-camphor has a significant effect on the on reaction but no effect on the off reaction. Analyzing these thermodynamic features on the basis of the physical chemistry in the solution reaction, it was found that these characteristic profiles arise from the difference in the global structural change between the proteins. Namely, during the equilibrium process of the CO binding, this structural change is accompanied by a larger increase in the degree of freedom in P-450cam than in Mb. We discussed the correlations between the structural changes and their biological significance.

Camphor↗
PubMed1996

From kinetics and thermodynamics of GABAA receptor binding to ionophore function.

The time- and temperature-dependencies of binding are overviewed for the benzodiazepine, GABA and convulsant binding sites of the GABAA receptor-ionophore complex. Kinetic separation of the dissociation phases of a beta-carboline inverse agonist demonstrated the heterogeneity of its binding sites. The kinetics and thermodynamics of benzodiazepine binding alone do not correlate with ionophore function. The majority of the data suggest that agonist- and antagonist-preferring conformations exist for GABAA receptors. The high affinity binding of GABAA antagonists (SR 95531 and bicuculline) corresponds to the (super) low affinity binding of GABA. The correlation between the thermodynamic parameters of binding and efficacies common for GABAA and glycine receptor agonists and antagonists supports the functional similarities of these anionophore complexes. Binding kinetics of the bicyclic cage convulsants show several correlations with ionophore function because the convulsant sites are most intimately coupled to the ion channels. Kinetic interactions of the convulsant sites with the binding sites of benzodiazepines, GABA and central depressants have revealed several pharmacologically relevant allosteric GABAergic modulatory effects. Arrhenius analysis, Hammond's postulate and transition state theory were applied for the dissociation of convulsants. A kinetic model of interconvertible multiaffinity states of the convulsant sites shows correlations with the functional states of the GABAA ionophore.

Animals↗
PubMed1995

Principles of protein-protein recognition from structure to thermodynamics.

Specific recognition is illustrated by X-ray structures of protease-inhibitor, antigen-antibody and other high affinity complexes including five electron transfer complexes. We attempt to give a physical definition to affinity and specificity on the basis of these data. In a protein-protein complex, specific recognition results from the assembly of complementary surfaces into well-packed interfaces that cover about 1500 A2 and contain about ten hydrogen bonds. These interfaces are larger than between molecules in protein crystals, and smaller than between subunits in oligomeric proteins. We relate the size and chemical nature of interfaces in complexes to the thermodynamical parameters that characterize affinity: the heat capacity and free enthalpy (Gibbs energy) of dissociation at equilibrium, the activation free enthalpy for the dissociation reaction. The same structural and thermodynamical parameters are inadequate for representing the specificity of recognition. We propose instead to describe specificity with the help of statistical physics, and we illustrate the application of the random energy model to antigen-antibody recognition by analyzing results of computer simulations by docking.

Chemical Phenomena↗
PubMed1976

Thermodynamic investigations of proteins. I. Standard functions for proteins with lysozyme as an example.

A direct method is proposed for obtaining thermodynamic standard functions for native and denatured proteins using experimental data from scanning calorimetry, isothermal calorimetry and potentiometric titrations. The possibility of this approach is demonstrated on the example of lysozyme in the range of pH 1.5-7.0 and temperature 0-100 degrees C. Tests for the validity of the obtained functions of enthalpy and entropy are presented in the form of cyclic processes using experimental data obtained from thermodynamically different pathways. The Gibbs function is checked by comparison with results of an independent method. The methodic problems in determining and checking standard functions for proteins are discussed in detail.

Calorimetry↗
PubMed1976

Thermodynamic investigations of proteins. II. Calorimetric study of lysozyme denaturation by guanidine hydrochloride.

The thermodynamic parameters of the denaturation of lysozyme are determined at various temperatures (25-60 degrees C) by isothermal calorimetric titrations with guanidine hydrochloride (GuHCl) and by scanning calorimetry in the presence of GuHCl. An approach for the determination of the enthalpy of preferential binding of GuHCl is proposed. It has been shown from GuHCl denaturation experiments that the net enthalpies of denaturation and the denaturational change in the heat capacity of protein can be obtained if preferential binding is taken into consideration. These results are nearly the same as in the case of thermal denaturation in the absence of denaturants. It is concluded that the states of both heat- and GuHCl-denatured lysozyme are thermodynamically indistinguishable.

Binding Sites↗
PubMed1983

Efficiency of energy conversion in model biological pumps. Optimization by linear nonequilibrium thermodynamic relations.

Experimental investigations showed linear relations between flows and forces in some biological energy converters operating far from equilibrium. This observation cannot be understood on the basis of conventional nonequilibrium thermodynamics. Therefore, the efficiencies of a linear and a nonlinear mode of operation of an energy converter (a hypothetical redox-driven H+ pump) were compared. This comparison revealed that at physiological values of the forces and degrees of coupling (1) the force ratio permitting optimal efficiency was much higher in the linear than in the nonlinear mode and (2) the linear mode of operation was at least 10(6)-times more efficient that the nonlinear one. These observations suggest that the experimentally observed linear relations between flows and forces, particularly in the case of oxidative phosphorylation, may be due to a feedback regulation maintaining linear thermodynamic relations far from equilibrium. This regulation may have come about as the consequence of an evolutionary drive towards higher efficiency.

Energy Metabolism↗
PubMed1986

Conformational species of gramicidin A in non-polar solvent. A kinetic and thermodynamic treatment in the absence and presence of phosphatidylcholine as studied by high-performance liquid chromatography.

A kinetic and thermodynamic study has been carried out to characterize quantitatively the conformational equilibrium of gramicidin A (GA) in tetrahydrofuran at different peptide concentrations in the absence and presence of egg yolk phosphatidylcholine by using size-exclusion high-performance liquid chromatographic analysis. In the absence of lipid, the experimental data fit a simple dimer-monomer equilibrium, the rate and equilibrium constants for the dissociation process being (1.6 +/- 0.7) X 10(-7) s-1 and (8.5 +/- 0.3) X 10(-6) M, respectively. A higher extent of monomerization and a decrease in the time required for reaching equilibrium are detected in the presence of phospholipid, the kinetic and thermodynamic effects depending on both lipid and GA concentrations. In order to account for these observations a cyclic equilibrium mechanism is proposed which is analysed in terms of four conformational species, namely, free monomer, free dimer, lipid-bound monomer and lipid-bound dimer. The results obtained are discussed in relation to recent literature data on lipid-protein interactions.

Chromatography, High Pressure Liquid↗
PubMed1988

Effect of sucrose on the dimerization of alpha-chymotrypsin. Allowance for thermodynamic nonideality arising from the presence of a small inert solute.

The space-filling effects of sucrose on the dimerization of alpha-chymotrypsin have been investigated by sedimentation equilibrium studies on the enzyme in acetate-chloride buffer, pH 3.9, I 0.2. From the extent of enhancement of the apparent dimerization constant in the presence of 0.05-0.16 M sucrose, it is concluded that this effect of thermodynamic nonideality finds quantitative explanation in terms of excluded volume. However, the suggested approximation that the radius of an inert small solute would be sufficiently small to be neglected in the calculation of covolumes (D.J. Winzor and P.R. Wills, Biophys. Chem. 25 (1986) 243) has not withstood the more stringent test afforded by the present study of alpha-chymotrypsin dimerization. A value of 0.34 nm for the effective thermodynamic radius of sucrose was inferred from the covolume for self-interaction obtained by frontal gel chromatography on Sephadex G-10 under the conditions of the ultracentrifugal studies. Finally, results of sedimentation equilibrium experiments on alpha-chymotrypsin in the presence of 0.1 M glycerol were also shown to be consistent with interpretation in terms of the model of space-filling effects entailing complete exclusion of small solute from the hydrated protein domain.

Chymotrypsin↗
PubMed1989

Activation thermodynamics of the binding of carbon monoxide to horseradish peroxidase. Role of pressure, temperature and solvent.

The kinetics at 423 nm of the binding of carbon monoxide to ferrous horseradish peroxidase were studied as a function of three parameters: pressure (1-1200 bar), temperature (34 to -20 degrees C) and solvent (water, 40% ethylene glycol, 50% methanol) using a high-pressure stopped-flow apparatus. By using transition state theory the thermodynamic quantities delta V, delta S and delta H were determined under these different experimental conditions and were found to be greatly modulated by the physico-chemical parameters of the media. The results suggest that the macroscopic thermodynamic response is mainly controlled by the solvent. By adjusting two variables (among T, P, solvent), it is possible either to amplify or to cancel out the effect of the third.

Carbon Monoxide↗
PubMed1992

Thermodynamic model of cooperativity in a dimeric protein: unique and independent parameters formulation.

A model of the cooperative interaction of ligand binding to a dimeric protein is presented based upon the unique and independent parameters (UIP) thermodynamic formulation (Gutheil and McKenna, Biophys. Chem. 45 (1992) 171-179). The analysis is developed from an initial model which includes coupled conformational and ligand binding equilibria. This completely general model is then restricted to focus on conformationally mediated cooperative interactions between the ligands and the expressions for the apparent ligand binding constant and the apparent ligand-ligand interaction constant are derived. The conditions under which there is no cooperative interaction between the ligands are found as roots to a polynomial equation. Consideration of the distribution of species among the various conformational states in this general model leads to a set of inequalities which can be represented as a two dimensional plot of boundaries. By superimposing a contour plot of the value of the apparent ligand-ligand interaction constant over the plot of boundaries a complete graphical representation of this system is achieved similar to a phase diagram. It is found that the parameter space homologous to Koshland-Nemethy-Filmer type of model is most consistent with both positive and negative cooperativity in this model. The maximal amount of positive and negative cooperativity are found to be simple functions of Kc, the equilibrium constant associated with the change of a subunit and ligand from the unligated to ligated conformation. It is shown that under certain limiting conditions the apparent allosteric interaction between ligands is equal to the conformational interaction between subunits. The methods presented are generally applicable to the theoretical analysis of thermodynamic interactions in complex systems.

Kinetics↗