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PubMed1976

Thermodynamic fluctuations in protein molecules.

Apparently conflicting views of the physical nature of globular proteins, and other macromolecules, may be reconciled by consideration of the inevitable thermodynamic fluctuations inherent in microscopic systems. Discrete protein molecules, considered singly, undergo sizeable fluctuations in thermodynamic properties which are manifest in their stochastic properties. This is not incompatible with time-averaged studies of ensembles of proteins from which a more compact, rigid, and static view of these molecules may be obtained.

Proteins↗
PubMed1977

Thermodynamics of the self-association of glucagon.

In water, glucagon exists in an equilibrium between a trimer in which more than half of the peptide groups are in an alpha-helical configuration and a monomer which has a random coil configuration with few alpha-helical residues. The thermodynamics of this self-association have been evaluated by studying the temperature- and concentration-dependence of the mean residue ellipticity at 220 nm. The enthalpy and entropy changes of association were negative at all temperatures between 5 degrees and 50 degrees and had large negative temperature dependencies. Usually an association that involves nonpolar groups is considered to be driven by a positive entropy term. Such an explanation is not tenable in the case of glucagon. However, if the effects of nonpolar groups on the coil-to-helix transition of a polypeptide are included into the thermodynamic considerations of hydrophobic interactions, then the negative parameters observed for glucagon association can be readily understood. The hydrophobic interaction is therefore not necessarily controlled by the entropy change because, if there are significant conformational changes, the reaction may be controlled by the enthalpy change. Consequently, the more important parameter characteristic of all hydrophobic reactions is the heat capacity change.

Glucagon↗
PubMed1981

Mosaic nonequilibrium thermodynamics describes biological energy transduction.

A procedure, called "mosaic nonequilibrium thermodynamics," for describing ion movement and energy transduction in biological membranes is tested in a model system: bacteriorhodopsin liposomes. The important steps in the theoretical derivations are summarized; one of the experimental tests of the postulated fundamental flow-force relationships is shown. Furthermore, how the quantitative method, even if used only qualitatively, facilitates analysis and understanding of experimental results (in this case, the effect of medium composition on the development of pH gradient and membrane potential in the bacteriorhodopsin liposomes) is shown. The main advantage of this method lies in its quantitative description of the effect of variation of system parameters on the performance of, in this case, the reconstituted proton pump bacteriorhodopsin. As an example, the method is shown to explain quantitatively the dependence of the steady-state pH gradient on the light intensity. Even in more refined analyses of experiments, the quantitative theoretical description is in full accordance with the experimental results; this is illustrated by considering the effect of valinomycin on the dependence of the initial rate of proton uptake into bacteriorhodopsin liposomes on light intensity. It is concluded that mosaic nonequilibrium thermodynamics describes ion movement and energy transduction in the model system of bacteriorhodopsin liposomes and, therefore, may be applied to any other biological system performing such processes.

Bacteriorhodopsins↗
PubMed1983

Thermodynamic efficiency of microbial growth is low but optimal for maximal growth rate.

Thermodynamic efficiency of microbial growth on substrates that are more oxidized than biomass approaches 24%. This is the theoretical value for a linear energy converter optimized for maximal output flow at optimal efficiency. For growth on substrates more reduced than biomass, thermodynamic efficiencies correspond to those predicted for optimization to maximal growth rate (or yield) only.

Bacteria↗
PubMed1983

Thermodynamics of assembly of Escherichia coli aspartate transcarbamoylase.

Reaction microcalorimetry and potentiometry have been used to define the thermodynamics of assembly of Escherichia coli aspartate transcarbamoylase (aspartate carbamoyltransferase, carbamoylphosphate:L-aspartate carbamoyltransferase, EC 2.1.3.2) from its catalytic and regulatory subunits and the linkage between assembly and proton binding. Over the pH range 7-9.5 and the temperature range 15-30 degrees C, assembly is characterized by negative enthalpy and heat capacity changes and positive entropy changes. The dependence of the enthalpy and entropy changes on pH is complex; however, the negative heat capacity change results in both quantities becoming more negative with increasing temperature. Assembly is linked to the binding of protons; the effects observed can be fit to models involving six or more ionizable groups with pK values of 7.3-7.4, 8.5-8.8, and 9.2-9.5, which ionize cooperatively. Contributions from additional groups cannot be ruled out and are in fact expected. The overall pattern of thermodynamic effects implies a complex set of intersubunit interactions. Protonation reactions and increased hydrogen bonding are likely to be the major sources of the negative enthalpy change; however, the negative heat capacity change results primarily from changes in solvent structure associated with hydrophobic and electrostatic bond formation with changes in low-frequency vibrational modes making a secondary contribution. Similarly, the relatively small entropy change observed within the temperature range examined probably reflects the balance between positive contributions from increased hydrophobic and electrostatic bonding and negative contributions from increased hydrogen bonding and damping of low-frequency vibrational modes.

Aspartate Carbamoyltransferase↗
PubMed1988

Canonical formulation of linkage thermodynamics.

The canonical structure of the group of thermodynamic potentials obtained from the energy of a physico-chemical system removes any possible distinction between physical and chemical binding phenomena. Transformations of these potentials by means of Jacobians give linkage relations for equilibrium thermodynamics. Linkage matrices are introduced to explore the functional properties of a biological macromolecule. They provide a quantitative basis for a broader approach and understanding of generalized binding phenomena.

Carbon Monoxide↗
PubMed1989

Monte Carlo description of oligoelectrolyte properties of DNA oligomers: range of the end effect and the approach of molecular and thermodynamic properties to the polyelectrolyte limits.

Applications of the grand canonical Monte Carlo method demonstrate the importance of end effects on fundamental molecular and thermodynamic properties of oligoelectrolyte solutions. Simulations are carried out for a series of solutions containing double-helical DNA oligomers of varying numbers of phosphate charges N (8 less than or equal to N less than or equal to 100) and univalent electrolyte at fixed activity (a +/- = 1.76 mmol/dm3). These results are used to evaluate as follows: C+N(a), the local concentration of cations at various axial positions along the oligomer surface; C+N(a), the axial average of these concentrations; TN, the preferential interaction coefficient expressed per oligomer charge, which is directly related to the fractional thermodynamic extent of association of counterions. A sufficiently long oligomer (N greater than or equal to 48 under the conditions simulated) is characterized by an interior region over which C+N(a) is uniform and equal to C+ infinity (a), the polyion limit. This interior region is flanked by two symmetric terminal regions, in which C+N(a) varies linearly with axial position from the end of the oligomer to a distance approximately 18 monomer units (approximately 3.1 nm) from that end. For long oligomers, the characteristics of the terminal regions [length and axial profile of C+N(a)] do not vary with N and, by inference, also pertain to the polyion under the same conditions. Both C+N(a) and TN approach their polyelectrolyte limits as linear functions of 1/N. These linear dependences can be attributed to the increasing predominance of the contribution due to the polyion-like interior of the oligomer as N increases.

DNA↗
PubMed1989

Predictions of thermodynamic efficiency in a pumped biochemical reaction.

We propose and analyze a possible experimental system for the investigation of the thermodynamic efficiency of generating biochemical gradients. We investigate the efficiency of a model pump that uses 6-phosphofructokinase (EC 2.7.1.11, an enzyme that exhibits highly nonlinear kinetics), chromatophores from Rhodobacter sphaeroides, and light to generate a biochemical gradient. We analyze the experimental system and an equivalent alternative configuration and show that the establishment and maintenance of a concentration gradient across a membrane is thermodynamically equivalent to the establishment and maintenance of a stationary state in a single-phase, isothermal, open, homogeneous reaction system. With a constant input of light, the system can exist in a stable node (a stable steady state), a stable focus (upon perturbation from its steady state, the system returns to its steady state with an oscillatory component), and a stable limit cycle (at steady state the system exhibits stable oscillations). We investigate the efficiency of the system with both steady and oscillatory light input and observe efficiency changes that depend upon the autonomous state of the system and the frequency and amplitude of the periodic light input. When the system is in a stable focus, an efficiency maximum is seen when the system is perturbed at its resonant frequency. When the system is in a stable limit cycle, efficiency increases are seen near the 1:3, 1:2, and 2:1 entrainment regions and an efficiency decrease is seen near the 1:1 entrainment region. We further calculate various contributions to the efficiency: the phase shift of the force and flux, the magnitude of the response to the perturbation, and changes in the average values of the force and flux during a perturbation. We show that all three changes contribute to the overall changes in efficiency, but increases and decreases in the average force make the largest contributions.

Kinetics↗
PubMed1992

Thermodynamics and structure of a DNA tetraplex: a spectroscopic and calorimetric study of the tetramolecular complexes of d(TG3T) and d(TG3T2G3T).

We report a combined thermodynamic and structural characterization of a DNA tetraplex. Using spectroscopic and calorimetric techniques, we demonstrate that d(TG3T) and d(TG3T2G3T), in the presence of K+, form stable tetramolecular complexes. From differential scanning calorimetry measurements, we obtain the following thermodynamic profiles for formation of each tetraplex at 25 degrees C: delta G degrees = -6.9 kcal/mol of tetraplex (or -2.3 kcal/mol of tetrad; 1 cal = 4.184 J), delta H degrees = -62.6 kcal/mol of tetraplex (or -20.9 kcal/mol of tetrad), and delta S degrees = -186.9 cal.K-1.mol-1 of tetraplex (or -62.3 cal.K-1.mol-1 of tetrad) for the d(TG3T) tetraplex; and delta G degrees = -20.2 kcal/mol of tetraplex (or -3.4 kcal/mol of tetrad), delta H degrees = -123.2 kcal/mol of tetraplex (or -20.5 kcal/mol of tetrad), and delta S degrees = -346.0 cal.K-1.mol-1 of tetraplex (or -57.7 cal.K-1.mol-1 of tetrad) for the d(TG3T2G3T) tetraplex. These data demonstrate that at 25 degrees C a G-tetrad can exhibit considerable stability, comparable to or even exceeding that of most Watson-Crick nearest-neighbor interactions, with this stability resulting from a very favorable enthalpy of formation. Temperature-dependent CD measurements reveal that the melting temperatures of both tetraplexes exhibit unusually low salt dependences. This unexpected behavior may reflect a diminished charge density due to bound K+ ions. For each complex, the Na+ and K+ forms exhibit drastically different isothermal and temperature-dependent CD profiles, with the K+ forms of each tetraplex melting more sharply and at a higher temperature than the Na+ forms. Using one- and two-dimensional NMR techniques, we show that the strands in the tetramolecular complex of d(TG3T), K+ are all parallel and that the guanine glycosidic conformations are all anti.

Base Sequence↗
PubMed1998

On the thermodynamic hypothesis of protein folding.

The validity of the thermodynamic hypothesis of protein folding was explored by simulating the evolution of protein sequences. Simple models of lattice proteins were allowed to evolve by random point mutations subject to the constraint that they fold into a predetermined native structure with a Monte Carlo folding algorithm. We employed a simple analytical approach to compute the probability of violation of the thermodynamic hypothesis as a function of the size of the protein, the fraction of the total number of possible conformations which are kinetically accessible, and the roughness of the free-energy landscape. It was found that even if the folding is under kinetic control, the sequence will evolve so that the native state is most often the state of minimum free energy.

Kinetics↗
PubMed1998

A thermodynamic analysis of the sequence-specific binding of RNA by bacteriophage MS2 coat protein.

Most mutations in the sequence of the RNA hairpin that specifically binds MS2 coat protein either reduce the binding affinity or have no effect. However, one RNA mutation, a uracil to cytosine change in the loop, has the unusual property of increasing the binding affinity to the protein by nearly 100-fold. Guided by the structure of the protein-RNA complex, we used a series of protein mutations and RNA modifications to evaluate the thermodynamic basis for the improved affinity: The tight binding of the cytosine mutation is due to (i) the amino group of the cytosine residue making an intra-RNA hydrogen bond that increases the propensity of the free RNA to adopt the structure seen in the complex and (ii) the increased affinity of hydrogen bonds between the protein and a phosphate two bases away from the cytosine residue. The data are in good agreement with a recent comparison of the cocrystal structures of the two complexes, where small differences in the two structures are seen at the thermodynamically important sites.

Binding Sites↗
PubMed1998

Thermodynamics of electron transfer in Escherichia coli cytochrome bo3.

The proton translocation mechanism of the Escherichia coli cytochrome bo3 complex is intimately tied to the electron transfers within the enzyme. Herein we evaluate two models of proton translocation in this enzyme, a cytochrome c oxidase-type ion-pump and a Q-cycle mechanism, on the basis of the thermodynamics of electron transfer. We conclude that from a thermodynamic standpoint, a Q-cycle is the more favorable mechanism for proton translocation and is likely occurring in the enzyme.

Allosteric Regulation↗
PubMed1995

Kinetics and thermodynamics of virus binding to receptor. Studies with rhinovirus, intercellular adhesion molecule-1 (ICAM-1), and surface plasmon resonance.

We have studied the kinetics and thermodynamics of a virus interacting with its receptor using human rhinovirus serotype 3 (HRV3), soluble intercellular adhesion molecule-1 (ICAM-1, CD54) containing Ig superfamily domains 1-5 (sICAM-1), and surface plasmon resonance. There were two classes of binding sites for sICAM-1 on HRV3, each comprising about 50% of the total sites, with association rate constants of 2450 +/- 300 and 134 +/- 11 M-1 s-1. These rates are low, consistent with binding to a relatively inaccessible site in the rhinovirus canyon. By contrast, three monoclonal antibodies bound to sICAM-1 with a single rate constant of 17,000-48,000 M-1 s-1. The dissociation rate constant for HRV3 was 1.7 +/- 0.1 x 10(-3) s-1, giving calculated dissociation constants of 0.7 +/- 0.1 and 12.5 +/- 1.2 microM. Agreement was good with saturation binding in solution, which showed two sites of similar abundance with KD of 0.55 +/- 0.2 and 5.7 +/- 2.0 microM. A bivalent chimera of ICAM-1 with the IgA1 Fc region bound with KD = 50 and 410 nM, showing 17-fold enhanced affinity. Lowering pH from 8.0 to 6.0 reduced affinity by approximately 50-fold, primarily by reducing the on rate. Thermodynamic measurements showed that binding of ICAM-1 to HRV3 is endothermic, by contrast to binding to monoclonal antibody. The heat that is absorbed of 3.5 and 6.3 kcal/mol for the two classes of ICAM-1 binding sites may contribute to receptor-mediated disruption of virions, which has an activation energy of about 42 kcal/mol.

Animals↗
PubMed1998

Familial mutations and the thermodynamic stability of the recombinant human prion protein.

Hereditary forms of human prion disease are linked to specific mutations in the PRNP gene. It has been postulated that these mutations may facilitate the pathogenic process by reducing the stability of the prion protein (PrP). To test this hypothesis, we characterized the recombinant variants of human PrP(90-231) containing point mutations corresponding to Gerstmann-Straussler-Scheinker disease (P102L), Creutzfeld-Jakob disease (E200K), and fatal familial insomnia (M129/D178N). The first two of these mutants could be recovered form from the periplasmic space of Escherichia coli in a soluble form, whereas the D178N variant aggregated into inclusion bodies. The secondary structure of the two soluble variants was essentially identical to that of the wild-type protein. The thermodynamic stability of these mutants was assessed by unfolding in guanidine hydrochloride and thermal denaturation. The stability properties of the P102L variant were indistinguishable from those of wild-type PrP, whereas the E200K mutation resulted in a very small destabilization of the protein. These data, together with the predictive analysis of other familial mutations, indicate that some hereditary forms of prion disease cannot be rationalized using the concept of mutation-induced thermodynamic destabilization of the cellular prion protein.

Creutzfeldt-Jakob Syndrome↗
PubMed1998

Forcing thermodynamically unfolded proteins to fold.

A growing number of biologically important proteins have been identified as fully unfolded or partially disordered. Thus, an intriguing question is whether such proteins can be forced to fold by adding solutes found in the cells of some organisms. Nature has not ignored the powerful effect that the solution can have on protein stability and has developed the strategy of using specific solutes (called organic osmolytes) to maintain the structure and function cellular proteins in organisms exposed to denaturing environmental stresses (Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D., and Somero, G. N. (1982) Science 217, 1214-1222). Here, we illustrate the extraordinary capability of one such osmolyte, trimethylamine N-oxide (TMAO), to force two thermodynamically unfolded proteins to fold to native-like species having significant functional activity. In one of these examples, TMAO is shown to increase the population of native state relative to the denatured ensemble by nearly five orders of magnitude. The ability of TMAO to force thermodynamically unstable proteins to fold presents an opportunity for structure determination and functional studies of an important emerging class of proteins that have little or no structure without the presence of TMAO.

Methylamines↗
PubMed1999

Poly(L-lysine)-graft-dextran copolymer promotes pyrimidine motif triplex DNA formation at physiological pH. Thermodynamic and kinetic studies.

Extreme instability of pyrimidine motif triplex DNA at physiological pH severely limits its use for artificial control of gene expression in vivo. Stabilization of the pyrimidine motif triplex at physiological pH is therefore of great importance in improving its therapeutic potential. To this end, isothermal titration calorimetry interaction analysis system and electrophoretic mobility shift assay have been used to explore the thermodynamic and kinetic effects of our previously reported triplex stabilizer, poly (L-lysine)-graft-dextran (PLL-g-Dex) copolymer, on pyrimidine motif triplex formation at physiological pH. Both the thermodynamic and kinetic analyses have clearly indicated that in the presence of the PLL-g-Dex copolymer, the binding constant of the pyrimidine motif triplex formation at physiological pH was about 100 times higher than that observed without any triplex stabilizer. Of importance, the triplex-promoting efficiency of the copolymer was more than 20 times higher than that of physiological concentrations of spermine, a putative intracellular triplex stabilizer. Kinetic data have also demonstrated that the observed copolymer-mediated promotion of the triplex formation at physiological pH resulted from the considerable increase in the association rate constant rather than the decrease in the dissociation rate constant. Our results certainly support the idea that the PLL-g-Dex copolymer could be a key material and may eventually lead to progress in therapeutic applications of the antigene strategy in vivo.

DNA↗
PubMed2000

Thermodynamic consequences of grafting enhanced affinity toward the mutated antigen onto an antibody. The case of anti-lysozyme antibody, HyHEL-10.

In order to address the mechanism of enhancement of the affinity of an antibody toward an antigen from a thermodynamic viewpoint, anti-hen lysozyme (HEL) antibody HyHEL-10, which also recognize the mutated antigen turkey lysozyme (TEL) with reduced affinity, was examined. Grafting high affinity toward TEL onto HyHEL-10 was performed by saturation mutagenesis into four residues (Tyr(53), Ser(54), Ser(56), and Tyr(58)) in complementarity-determining region 2 of the heavy chain (CDR-H2) followed by selection with affinity for TEL. Several clones enriched have a Phe residue at site 58. Thermodynamic analyses showed that the clones selected had experienced a greater than 3-fold affinity increase toward TEL in comparison with wild-type Fv, originating from an increase in negative enthalpy change. Substitution of HyHEL-10 HTyr(58) with Phe led to the increase in negative enthalpy change and to almost identical affinity for TEL in comparison with mutants selected, indicating that mutations at other sites decrease the entropy loss despite little contribution to the affinity for TEL. These results suggest that the affinity of an antibody toward the antigen is enhanced by the increase in enthalpy change by some limited mutation, and excess entropy loss due to the mutation is decreased by other energetically neutral mutations.

Animals↗
PubMed2000

Thermodynamic linkage between the S1 site, the Na+ site, and the Ca2+ site in the protease domain of human coagulation factor xa. Studies on catalytic efficiency and inhibitor binding.

The serine protease domain of factor Xa (FXa) contains a sodium as well as a calcium-binding site. Here, we investigated the functional significance of these two cation-binding sites and their thermodynamic links to the S1 site. Kinetic data reveal that Na(+) binds to the substrate bound FXa with K(d) approximately 39 mm in the absence and approximately 9.5 mm in the presence of Ca(2+). Sodium-bound FXa (sodium-Xa) has approximately 18-fold increased catalytic efficiency ( approximately 4.5-fold decrease in K(m) and approximately 4-fold increase in k(cat)) in hydrolyzing S-2222 (benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide), and Ca(2+) further increases this k(cat) approximately 1.4-fold. Ca(2+) binds to the protease domain of substrate bound FXa with K(d) approximately 705 microm in the absence and approximately 175 microm in the presence of Na(+). Ca(2+) binding to the protease domain of FXa (Xa-calcium) has no effect on the K(m) but increases the k(cat) approximately 4-fold in hydrolyzing S-2222, and Na(+) further increases this k(cat) approximately 1.4-fold. In agreement with the K(m) data, sodium-Xa has approximately 5-fold increased affinity in its interaction with p-aminobenzamidine (S1 site probe) and approximately 4-fold increased rate in binding to the two-domain tissue factor pathway inhibitor; Ca(2+) (+/-Na(+)) has no effect on these interactions. Antithrombin binds to Xa-calcium with a approximately 4-fold faster rate, to sodium-Xa with a approximately 24-fold faster rate and to sodium-Xa-calcium with a approximately 28-fold faster rate. Thus, Ca(2+) and Na(+) together increase the catalytic efficiency of FXa approximately 28-fold. Na(+) enhances Ca(2+) binding, and Ca(2+) enhances Na(+) binding. Further, Na(+) enhances S1 site occupancy, and S1 site occupancy enhances Na(+) binding. Therefore, Na(+) site is thermodynamically linked to the S1 site as well as to the protease domain Ca(2+) site, whereas Ca(2+) site is only linked to the Na(+) site. The significance of these findings is that during physiologic coagulation, most of the FXa formed will exist as sodium-Xa-calcium, which has maximum biologic activity.

4-Aminobenzoic Acid↗