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PubMed2001

Thermodynamic stability of base pairs between 2-hydroxyadenine and incoming nucleotides as a determinant of nucleotide incorporation specificity during replication.

We investigated the thermodynamic stability of double-stranded DNAs with an oxidative DNA lesion, 2-hydroxyadenine (2-OH-Ade), in two different sequence contexts (5'-GA*C-3' and 5'-TA*A-3', A* represents 2-OH-Ade). When an A*-N pair (N, any nucleotide base) was located in the center of a duplex, the thermodynamic stabilities of the duplexes were similar for all the natural bases except A (N = T, C and G). On the other hand, for the duplexes with the A*-N pair at the end, which mimic the nucleotide incorporation step, the stabilities of the duplexes were dependent on their sequence. The order of stability is T > G > C >> A in the 5'-GA*C-3' sequences and T > A > C > G in the 5'-TA*A-3' sequences. Because T/G/C and T/A are nucleotides incorporated opposite to 2-OH-Ade in the 5'-GA*C-3' and 5'-TA*A-3' sequences, respectively, these results agree with the tendency of mutagenic misincorporation of the nucleotides opposite to 2-OH-Ade in vitro. Thus, the thermodynamic stability of the A*-N base pair may be an important factor for the mutation spectra of 2-OH-Ade.

Base Pairing↗
PubMed2002

Determination of base and backbone contributions to the thermodynamics of premelting and melting transitions in B DNA.

In previous papers of this series the temperature-dependent Raman spectra of poly(dA).poly(dT) and poly(dA-dT).poly(dA-dT) were used to characterize structurally the melting and premelting transitions in DNAs containing consecutive A.T and alternating A.T/T.A base pairs. Here, we describe procedures for obtaining thermodynamic parameters from the Raman data. The method exploits base-specific and backbone-specific Raman markers to determine separate thermodynamic contributions of A, T and deoxyribosyl-phosphate moieties to premelting and melting transitions. Key findings include the following: (i) Both poly(dA).poly(dT) and poly(dA-dT). poly(dA-dT) exhibit robust premelting transitions, due predominantly to backbone conformational changes. (ii) The significant van't Hoff premelting enthalpies of poly(dA).poly(dT) [DeltaH(vH)(pm) = 18.0 +/- 1.6 kcal x mol(-1) (kilocalories per mole cooperative unit)] and poly(dA-dT).poly(dA-dT) (DeltaH(vH)(pm) = 13.4 +/- 2.5 kcal x mol(-1)) differ by an amount (approximately 4.6 kcal x mol(-1)) estimated as the contribution from three-centered inter-base hydrogen bonding in (dA)(n).(dT)(n) tracts. (iii) The overall stacking free energy of poly(dA). poly(dT) [-6.88 kcal x mol(bp)(-1) (kilocalories per mole base pair)] is greater than that of poly(dA-dT). poly(dA-dT) (-6.31 kcal x mol(bp)(-1)). (iv) The difference between stacking free energies of A and T is significant in poly(dA).poly(dT) (DeltaDeltaG(st) = 0.8 +/- 0.3 kcal. mol(bp)(-1)), but marginal in poly(dA-dT).poly(dA-dT) (DeltaDeltaG(st) = 0.3 +/- 0.3 kcal x mol(bp)(-1)). (v) In poly(dA). poly(dT), the van't Hoff parameters for melting of A (DeltaH(vH)(A) = 407 +/- 23 kcal.mol(-1), DeltaS(vH)(A) = 1166 +/- 67 cal. degrees K(-1) x mol(-1), DeltaG(vH(25 degrees C))(A) = 60.0 +/- 3.2 kcal x mol(-1)) are clearly distinguished from those of T (DeltaH(vH)(T) = 185 +/- 38 kcal x mol(-1), DeltaS(vH)(T) = 516 +/- 109 cal. degrees K(-1) x mol(-1), DeltaG(vH(25 degrees C))(T) = 27.1 +/- 5.5 kcal x mol(-1)). (vi) Similar relative differences are observed in poly(dA-dT). poly(dA-dT) (DeltaH(vH)(A) = 333 +/- 54 kcal x mol(-1), DeltaS(vH)(A) = 961 +/- 157 cal. degrees K(-1) x mol(-1), DeltaG(vH(25 degrees C))(A) = 45.0 +/- 7.6 kcal x mol(-1); DeltaH(vH)(T) = 213 +/- 30 kcal x mol(-1), DeltaS(vH)(T) = 617 +/- 86 cal. degrees K(-1) x mol(-1), DeltaG(vH(25 degrees C))(T) = 29.3 +/- 4.9 kcal x mol(-1)). The methodology employed here distinguishes thermodynamic contributions of base stacking, base pairing and backbone conformational ordering in the molecular mechanism of double-helical B DNA formation.

Base Composition↗
PubMed2003

NTDB: Thermodynamic Database for Nucleic Acids, Version 2.0.

The second release of Thermodynamic Database for Nucleic Acids, NTDB 2.0, includes more than 4600 entries (250% increase over release 1.0). It contains sequence types and details of several thermodynamic parameters (enthalpy, DeltaH; entropy, DeltaS; Gibbs free energy, DeltaG; melting temperature, T(m)), experimental models and methods for extracting thermodynamic parameters, buffer conditions as well as all relevant literature information. In addition, the database statistics and references related to NTDB are included. Information on normal and modified nucleobases and nucleosides are collected in a new section 'Nucleoside' whereby data collected thus far will be release in NTDB 2.0. The NTDB is freely available at http://ntdb.chem.cuhk.edu.hk.

Databases, Nucleic Acid↗
PubMed2003

Thermodynamic calculations and statistical correlations for oligo-probes design.

Optimization of probe design for array-based experiments requires improved predictability of oligonucleotide hybridization behavior. Currently, designing oligonucleotides capable of interacting efficiently and specifically with the relevant target is not a routine procedure. Multiple examples demonstrate that oligonucleotides targeting different regions of the same RNA differ in their hybridization ability. The present work shows how thermodynamic evaluations of oligo-target duplex or oligo self-structure stabilities can facilitate probe design. Statistical analysis of large sets of hybridization data reveals that thermodynamic evaluation of oligonucleotide properties can be used to avoid poor RNA binders. Thermodynamic criteria for the selection of 20 and 21mers, which, with high probability, interact efficiently and specifically with their targets, are suggested. The design of longer oligonucleotides can also be facilitated by the same calculations of DeltaG(o) (T) values for oligo-target duplex or oligo self-structure stabilities and similar selection schemes.

Nucleic Acid Hybridization↗
PubMed2004

ProTherm, version 4.0: thermodynamic database for proteins and mutants.

Release 4.0 of ProTherm, thermodynamic database for proteins and mutants, contains approximately 14,500 numerical data (approximately 450% of the first version) of several thermodynamic parameters along with experimental methods and conditions, and structural, functional and literature information. The sequence and structural information of proteins is connected with thermodynamic data through links between entries in Protein Data Bank, Protein Information Resource and SWISS-PROT and the data in ProTherm. We have separated the Gibbs free energy change obtained at extrapolated temperature from the data on denaturation temperature measured by the thermal denaturation method. We have added the statistics of amino acid replacements and links to homologous structures to each protein. Further, we have improved the search and display options to enhance search capability through the web interface. ProTherm is freely available at http://gibk26. bse.kyutech.ac.jp/jouhou/Protherm/protherm.html.

Animals↗
PubMed2006

Predicting RNA pseudoknot folding thermodynamics.

Based on the experimentally determined atomic coordinates for RNA helices and the self-avoiding walks of the P (phosphate) and C4 (carbon) atoms in the diamond lattice for the polynucleotide loop conformations, we derive a set of conformational entropy parameters for RNA pseudoknots. Based on the entropy parameters, we develop a folding thermodynamics model that enables us to compute the sequence-specific RNA pseudoknot folding free energy landscape and thermodynamics. The model is validated through extensive experimental tests both for the native structures and for the folding thermodynamics. The model predicts strong sequence-dependent helix-loop competitions in the pseudoknot stability and the resultant conformational switches between different hairpin and pseudoknot structures. For instance, for the pseudoknot domain of human telomerase RNA, a native-like and a misfolded hairpin intermediates are found to coexist on the (equilibrium) folding pathways, and the interplay between the stabilities of these intermediates causes the conformational switch that may underlie a human telomerase disease.

Animals↗
PubMed1976

Thermodynamic characteristics of the adsorption of sulfanilamide, phenol, and n-butanol on bio-gel beads.

The thermodynamic properties of the adsorption of sulfanilamide, phenol and n-butanol on Bio-Gel beads have been studied. Bio-Gel was chosen as the adsorbent as it possesses both hydrophobic and hydrophilic sites on its surface. Adsorption of the former two adsorbates was found to be exothermic, and the relevant thermodynamic parameters at 20 degrees are in the ranges: deltaH degrees = -2.7 to -5.4 kcal/mole; deltaF degrees = -6.0 to -7.6 kcal/mole; deltaS degrees = +7.7 to +11.6 e.u. In the presence of urea, adsorption of sulfanilamide and phenol was partially disrupted. This, together with the large entropy gain of the process, indicates that both hydrogen bonding and hydrophobic bonding contribute cooperatively to the adsorption. On the contrary, adsorption of n-butanol, which was not susceptible to urea, was an endothermic process with the parameters, deltaH degrees = +5.8kcal/mole, deltaF degrees = -1.8 kcal/mole, and deltaS = +26.1 E.U. at 20 degrees. These data conform to the thermodynamic properties of hydrophobic bond formation. Finally, possible implications of these data in the structural assembly of lipoprotein molecules are discussed.

Adsorption↗
PubMed2000

Structural and thermodynamic consequences of introducing alpha-aminoisobutyric acid in the S peptide of ribonuclease S.

The S protein-S peptide interaction is a model system to study binding thermodynamics in proteins. We substituted alanine at position 4 in S peptide by alpha-aminoisobutyric acid (Aib) to investigate the effect of this substitution on the conformation of free S peptide and on its binding to S protein. The thermodynamic consequences of this replacement were studied using isothermal titration calorimetry. The structures of the free and complexed peptides were studied using circular dichroic spectroscopy and X-ray crystallography, respectively. The alanine4Aib replacement stabilizes the free S peptide helix and does not perturb the tertiary structure of RNase S. Surprisingly, and in contrast to the wild-type S peptide, the DeltaG degrees of binding of peptide to S pro, over the temperature range 5-30 degrees C, is virtually independent of temperature. At 25 degrees C, the DeltaDeltaG degrees, DeltaDeltaH degrees, DeltaDeltaS and DeltaDeltaCp of binding are 0.7 kcal/mol, 2.8 kcal/mol, 6 kcal/mol x K and -60 kcal/mol x K, respectively. The positive value of DeltaDeltaS is probably due to a decrease in the entropy of uncomplexed alanine4Aib relative to the wild-type peptide. The positive value of DeltaDeltaH: degrees is unexpected and is probably due to favorable interactions formed in uncomplexed alanine4Aib. This study addresses the thermodynamic and structural consequences of a replacement of alanine by Aib both in the unfolded and complexed states in proteins.

Amino Acid Substitution↗
PubMed2005

Grid-based steered thermodynamic integration accelerates the calculation of binding free energies.

The calculation of binding free energies is important in many condensed matter problems. Although formally exact computational methods have the potential to complement, add to, and even compete with experimental approaches, they are difficult to use and extremely time consuming. We describe a Grid-based approach for the calculation of relative binding free energies, which we call Steered Thermodynamic Integration calculations using Molecular Dynamics (STIMD), and its application to Src homology 2 (SH2) protein cell signalling domains. We show that the time taken to compute free energy differences using thermodynamic integration can be significantly reduced: potentially from weeks or months to days of wall-clock time. To be able to perform such accelerated calculations requires the ability to both run concurrently and control in realtime several parallel simulations on a computational Grid. We describe how the RealityGrid computational steering system, in conjunction with a scalable classical MD code, can be used to dramatically reduce the time to achieve a result. This is necessary to improve the adoption of this technique and further allows more detailed investigations into the accuracy and precision of thermodynamic integration. Initial results for the Src SH2 system are presented and compared to a reported experimental value. Finally, we discuss the significance of our approach.

Computer Graphics↗
PubMed2006

Fluctuation theorems and the nonequilibrium thermodynamics of molecular motors.

The fluctuation theorems for the currents and the dissipated work are considered for molecular motors which are driven out of equilibrium by chemical reactions. Because of the molecular fluctuations, these nonequilibrium processes are described by stochastic models based on a master equation. Analytical expressions are derived for the fluctuation theorems, allowing us to obtain predictions on the work dissipated in the motor as well as on its rotation near and far from thermodynamic equilibrium. We show that the fluctuation theorems provide a method to determine the affinity or thermodynamic force driving the motor. This affinity is given in terms of the free enthalpy of the chemical reactions. The theorems are applied to the F1 rotary motor which turns out to be a stiff system typically functioning in the nonlinear regime of nonequilibrium thermodynamics. We show that this nonlinearity confers a robustness to the functioning of the molecular motor.

Computer Simulation↗
PubMed2006

Characterization of digital waveforms using thermodynamic analogs: detection of contrast-targeted tissue in vivo.

We describe characterization of backscatter from tumor tissue targeted with a nanoparticle-based ultrasound contrast agent in vivo using analogs of thermodynamic quantities. We apply these waveform characteristics to detection of tumor neovasculature in tumors implanted in athymic nude mice, which were imaged using a research ultrasound scanner over a 2-hour period after injection of alpha upsilon beta3-targeted perfluorocarbon nanoparticles. Images were constructed from backscattered ultrasound using two different approaches: fundamental B-mode imaging and a signal receiver based on a thermodynamic analog (H(C)). The study shows that the thermodynamic analog is capable of detecting differences in backscattered signals that are not apparent with the B-mode approach.

Algorithms↗
PubMed2004

Two different proteins that compete for binding to thrombin have opposite kinetic and thermodynamic profiles.

Thrombin binds thrombomodulin (TM) at anion binding exosite 1, an allosteric site far from the thrombin active site. A monoclonal antibody (mAb) has been isolated that competes with TM for binding to thrombin. Complete binding kinetic and thermodynamic profiles for these two protein-protein interactions have been generated. Binding kinetics were measured by Biacore. Although both interactions have similar K(D)s, TM binding is rapid and reversible while binding of the mAb is slow and nearly irreversible. The enthalpic contribution to the DeltaG(bind) was measured by isothermal titration calorimetry and van't Hoff analysis. The contribution to the DeltaG(bind) from electrostatic steering was assessed from the dependence of the k(a) on ionic strength. Release of solvent H(2)O molecules from the interface was assessed by monitoring the decrease in amide solvent accessibility at the interface upon protein-protein binding. The mAb binding is enthalpy driven and has a slow k(d). TM binding appears to be entropy driven and has a fast k(a). The favorable entropy of the thrombin-TM interaction seems to be derived from electrostatic steering and a contribution from solvent release. The two interactions have remarkably different thermodynamic driving forces for competing reactions. The possibility that optimization of binding kinetics for a particular function may be reflected in different thermodynamic driving forces is discussed.

Allosteric Regulation↗
PubMed2004

Thermodynamics and stability of a beta-sheet complex: molecular dynamics simulations on simplified off-lattice protein models.

We have performed discontinuous molecular dynamics simulations of the thermodynamics and stability of a tetrameric beta-sheet complex that contains four identical four-stranded antiparallel beta-sheet peptides. The potential used in the simulation is a hybrid Go-type potential characterized by the bias gap parameter g, an artificial measure of the preference of a model protein for its native state, and the intermolecular contact parameter eta, which measures the ratio of intermolecular to intramolecular native attractions. Despite the simplicity of the model, a complex set of thermodynamic transitions for the beta-sheet complex is revealed that shows there are three distinct oligomer (partially ordered, ordered, and highly ordered beta-sheet complex) states and four noninteracting monomers phases. The thermodynamic properties of the three oligomer states strongly depend on both the size of the intermolecular contact parameter eta and the temperature. The partially ordered beta-sheet complex is made up of four ordered globules and is observed at intermediate to large eta at high temperatures. The ordered beta-sheet complex contains four native beta-sheets and is located at small to intermediate eta at low temperatures in the phase diagram. The highly ordered beta-sheet complex has fully-stiff beta-sheet strands, the same as the global energy minimum structure, and is observed for all eta at low temperatures.

Computer Simulation↗
PubMed2005

Thermodynamic consequences of disrupting a water-mediated hydrogen bond network in a protein:pheromone complex.

The mouse pheromones (+/-)-2-sec-butyl-4,5-dihydrothiazole (SBT) and 6-hydroxy-6-methyl-3-heptanone (HMH) bind into an occluded hydrophobic cavity in the mouse major urinary protein (MUP-1). Although the ligands are structurally unrelated, in both cases binding is accompanied by formation of a similar buried, water-mediated hydrogen bond network between the ligand and several backbone and side chain groups on the protein. To investigate the energetic contribution of this hydrogen bond network to ligand binding, we have applied isothermal titration calorimetry to measure the binding thermodynamics using several MUP mutants and ligand analogs. Mutation of Tyr-120 to Phe, which disrupts a hydrogen bond from the phenolic hydroxyl group of Tyr-120 to one of the bound water molecules, results in a substantial loss of favorable binding enthalpy, which is partially compensated by a favorable change in binding entropy. A similar thermodynamic effect was observed when the hydrogen bonded nitrogen atom of the heterocyclic ligand was replaced by a methyne group. Several other modifications of the protein or ligand had smaller effects on the binding thermodynamics. The data provide supporting evidence for the role of the hydrogen bond network in stabilizing the complex.

Animals↗
PubMed2006

Thermodynamic stability of a cold-adapted protein, type III antifreeze protein, and energetic contribution of salt bridges.

A thermodynamic analysis of a cold-adapted protein, type III anti-freeze protein (AFP), was carried out. The results indicate that the folding equilibrium of type III AFP is a reversible, unimolecular, two-state process with no populated intermediates. Compared to most mesophilic proteins whose folding is two-state, the psychrophilic type III AFP has a much lower thermodynamic stability at 25 degrees C, approximately 3 kcal/mol, and presents a remarkably downshifted stability-temperature curve, reaching a maximum of 5 kcal/mol around 0 degrees C. Type III AFPs contain few and non-optimally distributed surface charges relative to their mesophilic homologs, the C-terminal domains of sialic acid synthases. We used thermodynamic double mutant cycles to evaluate the energetic role of every surface salt bridge in type III AFP. Two isolated salt bridges provided no contribution to stability, while the Asp36-Arg39 salt bridge, involved in a salt bridge network with the C-terminal carboxylate, had a substantial contribution (approximately 1 kcal/mol). However, this contribution was more than counteracted by the destabilizing effect of the Asp36 carboxylate itself, whose removal led to a net 30% increase in stability at 25 degrees C. This study suggests that type III AFPs may have evolved for a minimally acceptable stability at the restricted, low temperature range (around 0 degrees C) at which AFPs must function. In addition, it indicates that salt bridge networks are used in nature also for the stability of psychrophilic proteins, and has led to a type III AFP variant of increased stability that could be used for biotechnological purposes.

Algorithms↗
PubMed2000

Structure-based thermodynamic analysis of the dissociation of protein phosphatase-1 catalytic subunit and microcystin-LR docked complexes.

The relationship between the structure of a free ligand in solution and the structure of its bound form in a complex is of great importance to the understanding of the energetics and mechanism of molecular recognition and complex formation. In this study, we use a structure-based thermodynamic approach to study the dissociation of the complex between the toxin microcystin-LR (MLR) and the catalytic domain of protein phosphatase-1 (PP-1c) for which the crystal structure of the complex is known. We have calculated the thermodynamic parameters (enthalpy, entropy, heat capacity, and free energy) for the dissociation of the complex from its X-ray structure and found the calculated dissociation constant (4.0 x 10(-11)) to be in excellent agreement with the reported inhibitory constant (3.9 x 10(-11)). We have also calculated the thermodynamic parameters for the dissociation of 47 PP-1c:MLR complexes generated by docking an ensemble of NMR solution structures of MLR onto the crystal structure of PP-1c. In general, we observe that the lower the root-mean-square deviation (RMSD) of the docked complex (compared to the X-ray complex) the closer its free energy of dissociation (deltaGd(o)) is to that calculated from the X-ray complex. On the other hand, we note a significant scatter between the deltaGd(o) and the RMSD of the docked complexes. We have identified a group of seven docked complexes with deltaGd(o) values very close to the one calculated from the X-ray complex but with significantly dissimilar structures. The analysis of the corresponding enthalpy and entropy of dissociation shows a compensation effect suggesting that MLR molecules with significant structural variability can bind PP-1c and that substantial conformational flexibility in the PP-1c:MLR complex may exist in solution.

Bacterial Toxins↗
PubMed2000

A single disulfide bond restores thermodynamic and proteolytic stability to an extensively mutated protein.

The potential for engineering stable proteins with multiple amino acid substitutions was explored. Eleven lysine, five methionine, two tryptophan, one glycine, and three threonine substitutions were simultaneously made in barley chymotrypsin inhibitor-2 (CI-2) to substantially improve the essential amino acid content of the protein. These substitutions were chosen based on the three-dimensional structure of CI-2 and an alignment of homologous sequences. The initial engineered protein folded into a wild-type-like structure, but had a free energy of unfolding of only 2.2 kcal/mol, considerably less than the wild-type value of 7.5 kcal/mol. Restoration of the lysine mutation at position 67 to the wild-type arginine increased the free energy of unfolding to 3.1 kcal/mol. Subsequent cysteine substitutions at positions 22 and 82 resulted in disulfide bond formation and a protein with nearly wild-type thermodynamic stability (7.0 kcal/mol). None of the engineered proteins retained inhibitory activity against chymotrypsin or elastase, and all had substantially reduced inhibitory activity against subtilisin. The proteolytic stabilities of the proteins correlated with their thermodynamic stabilities. Reduction of the disulfide bond resulted in substantial loss of both thermodynamic and proteolytic stabilities, confirming that the disulfide bond, and not merely the cysteine substitutions, was responsible for the increased stability. We conclude that it is possible to replace over a third of the residues in CI-2 with minimal disruption of stability and structural integrity.

Amino Acid Sequence↗
PubMed1982

Optimization of bioavailability of topical steroids: thermodynamic control.

In theory, under strictly defined ideal conditions, the bioavailability of a drug from a topical formulation should depend only on the thermodynamic activity of the medicament in the base. We tested this fundamental postulate using a steroid as the test drug, formulated in a series of solutions and gels at 90% saturation, i.e., ideally at constant thermodynamic activity. The in vivo assessment method was the occluded vasoconstrictor test in humans. For most systems, this simple measure of thermodynamic activity correlated with drug bioavailability as assessed by the blanching response. Where there were differences, we have rationalized them in terms of penetration enhancement, irritancy, dehydration of the stratum corneum, or steroid binding in the base, although such factors have not been explicitly demonstrated.

Administration, Topical↗