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At least 19 recordsLinked to original sources
PubMed1974

The linkage between oxygenation and subunit dissociation in human hemoglobin.

The use of subunit dissociation as a means of probing intersubunit contact energy changes which accompany cooperative ligand binding has been studied for the case of human hemoglobin. An analysis is presented delineating the information that can be obtained from the linkage relationships between ligand binding and subunit dissociation of hemoglobin tetramers into dimers. The analysis defines (a) the variation of the saturation function, Y, with total protein concentration, (b) the variation of the subunit dissociation constant (x)K(2) with ligand concentration (X) and (c) the correlations between changes in dimer-dimer contact energy and the sequential ligand binding steps. Sensitivity of the linkage function has been explored by numerical simulation. It is shown that subunit dissociation may appreciably affect oxygenation curves under usual conditions of measurement and that relying solely on either (x)K(2) or Y may lead to incorrect picutres of the energetics, whereas the combination defines the system much more exactly.

Binding Sites↗
PubMed2003

Output energy changes of quartz contact probe for Er:YAG laser with tooth ablation.

The purpose of this study was to examine the output energy changes of the contact probe for Er:YAG laser with tooth ablation and evaluate the effect of contact surface polishing on output energy. The Er:YAG laser was irradiated to enamel of extracted human incisors for 100 min (5 min x 20 times). The output energy of contact probes was measured every 5 min (n = 3). After 100 min, the contact surfaces were polished using silicon carbide paper up to #1500, and the output energy of the probe was measured. The contact surfaces of the probes were observed and analyzed using an EPMA. After 100 min, the output energy showed 49.4% of the energy of an unused probe. After the contact surfaces were polished to #1500, the output energy returned to 96.4% of baseline. It is suggested that the output energy of the contact probe decreased with tooth ablation, and polishing of the contact surface was effective to regain the energy.

Aluminum Silicates↗
PubMed1976

Oxygenation-linked subunit interactions in human hemoglobin: experimental studies on the concentration dependence of oxygenation curves.

An experimental study on the concentration dependence of oxygenation curves for human hemoglobin has been carried out between 4 X 10(-8) M heme and 5 X 10(-4) M heme in 0.1 M tris(hydroxymehtyl)aminomethane hydrochloride, 0.1 M NaCl, 1 mM disodium ethylenediaminetetraacetic acid, pH 7.4, 21.5 degrees C. With decreasing hemoglobin concentration the curves show pronounced shifts in position and shape, consistent with dissociation of tetrameric hemoglobin into dimeric species of high affinity and low cooperativity. Combination of these data with independently determined values of dissociation constants for unliganded and fully liganded hemoglobin permits a resolution of the seven parameters necessary to define the linked binding and subunit association processes. The total oxygenation-linked subunit dissociation energy (6.34 kcal) was resolved into intersubunit contact energy changes between alphabeta dimers in tetrameric hemoglobin which accompany binding of the first, middle two, and last oxygen molecules. The resolution is accurate to within approximately +/-0.3 kcal. To within this limit the isolated dimers are found to bind oxygen noncooperatively and with the same affinity as isolated alpha and beta chains. Equally good fits to the data are obtained when dimers are slightly anticooperative. At least three major energetic states are apparently assumed by hemoglobin tetramers, with respect to the alpha1beta2 contact region, corresponding to (a) unliganded, (b) singly liganded, (c) triply and quadruply liganded species. The results do not establish whether these states may be assumed by a single molecule, or whether they arise as averages over a distrubution of conformational states. They do provide unequivocal evidence against a concerted transition at any particular binding step in a system with only two energetic states of tetramer (i.e., an all or none switchover between T and R states at a particular binding step).

Computers↗
PubMed2025

Quantifying Protein-Nucleic Acid Interactions for Engineering Useful CRISPR-Cas9 Genome-Editing Variants.

Numerous high-specificity Cas9 variants have been engineered for precision genome editing. These variants typically harbor multiple mutations designed to alter the Cas9-single guide RNA (sgRNA)-DNA complex interactions for reduced off-target cleavage. By dissecting the contributions of individual mutations, we attempt to derive principles for designing high-specificity Cas9 variants. Here, we computationally modeled the specificity harnessing mutations of the widely used Cas9 isolated from Streptococcus pyogenes (SpCas9) and investigated their individual mutational effects. We quantified the mutational effects in terms of energy and contact changes by comparing the wild-type and mutant structures. We found that these mutations disrupt the protein-protein or protein-DNA contacts within the Cas9-sgRNA-DNA complex. We also identified additional impacted amino acid sites via energy changes that constitute the structural microenvironment encompassing the focal mutation, giving insights into how the mutations contribute to the high-specificity phenotype of SpCas9. Our method outlines a strategy to evaluate mutational effects that can facilitate rational design for Cas9 optimization.

Gene Editing↗
PubMed1992

Molecular mechanics simulations of a conformational rearrangement of D-xylose in the active site of D-xylose isomerase.

A proposed reaction mechanism for the enzyme D-xylose isomerase involves the ring opening of the cyclic substrate with a subsequent conformational rearrangement to an extended open-chain form. Restrained energy minimization was used to simulate the rearrangement. In the ring-opening step, the substrate energy function was gradually altered from a cyclic to an open-chain form, with energy minimization after each change. The protein/sugar contact energy did not increase significantly during the process, showing that there was no steric hindrance to ring opening. The conformational rearrangement involves an alteration in the coordination of the substrate to metal ion [1], which was induced by gradually changing restraints on metal/ligand distances. By allowing varying amounts of flexibility in the protein and examining a simplified model system, the interactions of the sugar with metal ion [1] and its immediate ligands were found to be the most important contributors to the energy barrier for the change. Only small changes in the positions of protein atoms were required. The energy barrier to the rearrangement was estimated to be less than the Arrhenius activation energy for the enzymatic reaction. This is in accordance with experimental indications that the isomerization step is rate determining.

Aldose-Ketose Isomerases↗
PubMed1984

Water near intracellular surfaces.

In this paper we make the following points: Water is perturbed within several angstroms of the surfaces of soluble molecules. Removal of this water can require significant amounts of work, seen as an exponentially varying "hydration force" with respect to molecular separation. The favorable and specific attractions that occur in molecular assembly or in ligand binding imply that the specific association between the molecular surfaces is stronger than the association of those surfaces with water. The specificity of biochemical association is not simply a matter of protein-protein interaction but also of competing protein-water interactions. Small structural changes in molecular surfaces can evoke large changes in the contact energy of hydrated surfaces; surface hydration and the energetics of water displacement are a likely mechanism for the contact specificity of intracellular associations integrating the cell matrix.

Body Fluids↗
PubMed1996

Free energy simulations of axial contacts in sickle-cell hemoglobin.

Molecular dynamics simulations have been used to investigate the thermodynamic stability of axial contacts in sickle-cell hemoglobin (HbS). Free energy changes were evaluated for the point mutation beta 121 Glu --> Gln in the axial contact region of HbS crystals. The calculations predict a free energy change of-3.6 kcal/mol per contact for the mutation, which is in qualitative agreement with experimental observations of aggravated sickling found in the double mutant Hb D Los Angeles (beta 6 Glu --> Val. beta 121 Glu --> Gln) relative to HbS (beta 6 Glu --> Val). The beta 121 Glu is sequestered in a salt link with beta 17 Lys located on the same polypeptide chain, making the Glu interactions with its surroundings similar in aggregates and individual hemoglobins. Due to this cancellation of the large electrostatic Glu contributions, the weak nonspecific interactions between the Gln and the neighboring polypeptide chain are the main contributing factor to the enhanced aggregation of Hb D Los Angeles relative to HbS. Together with the previous study of the lateral contact [K. Kuczera et al. (1990) Proceedings of the National Academy of Science USA, Vol. 87, pp, 8481-8485], the present results provide a more complete picture of the forces driving the sickling aggregation. A comparison of different treatments of internal flexibility in free energy simulations and analysis of rate of convergence of the different calculated properties has also been performed.

Computer Simulation↗
PubMed1987

[Eukaryotic and prokaryotic DNA-polymerase. II. The role of internucleotide phosphate groups of a template in its binding with the enzyme].

The affinity of different ligands (phosphate, nucleoside monophosphates, oligonucleotides) to the template binding site of DNA polymerase alpha from human placenta was estimated. To this goal, dependences of rate of the enzyme inactivation by the affinity reagent d(pT)2pC[Pt2+(NH3)2OH](pT)7 on the concentration of these ligands as competitive inhibitors were determined. Minimal ligands capable to bind with the template site of DNA polymerase alpha were shown to be triethylphosphate (Kd 600 microM) and phosphate (Kd 53 microM). Ligand affinity increases by the factor 1.71 per added monomer unit from phosphate to d(pT) and then for oligothymidylates d(Tp)nT (n 1 to 14). The partial ethylation of phosphodiester groups does not change the efficiency of the oligothymidylate binding with the enzyme. However, the complete ethylation of these groups lowers affinity of the oligothymidylates to the enzyme by 7-9 times. The decrease is comparable with the change of Pt2+-decathymidylate affinity to the enzyme caused by Mn2+-ions. The data obtained led to suggestion that an electrostatic contact (most likely, Me2+-dependent) of phosphodiester group with the enzyme takes place. The type of contact is confirmed by Gibbs' energy change 1.1-1.4 kcal/mole. Formation of a hydrogen bond with the oxygen atom of P = O group of the same phosphate is also assumed (delta G =--4.4 . . .--4.5 kcal/mole). The other internucleotide phosphates and all bases of oligonucleotides form neither hydrogen bonds nor electrostatic contacts with the template binding site. Gibbs' energy changes by 0.32 kcal/mole when the template is lengthened by one unit. We suppose that this value characterizes the energy gain in the transition of oligonucleotide template from aquous medium to the hydrophobic environement of the enzyme active site. Comparison of Km values of oligothymidylates and their partially or completely ethylated analogues as templates in the reaction of DNA polymerization catalysed by DNA polymerase alpha from human placenta and Klenow's fragment of E. coli DNA polymerase I suggests a similar mechanism of template recognition by both enzymes.

DNA Polymerase I↗
PubMed1997

Analysis of protein-protein interactions and the effects of amino acid mutations on their energetics. The importance of water molecules in the binding epitope.

A modeling analysis has been conducted to assess the determinants of binding strength and specificity for three crystal complexes; the anti-hen egg white lysozyme antibody D1.3 complexed with hen egg white lysozyme (HEL), the D1.3 antibody complexed with the anti-lysozyme antibody E5.2, and barnase complexed with barstar. The strengths of individual binding components within these interfaces are evaluated using a model of binding free energy that is based on pairwise surface preferences. In all cases the energetics of binding are dominated by a relatively small number of interfacial residues that define the binding epitope. A precise geometric arrangement of these residues was not found; they were either localized to one region, or distributed throughout the binding interface. Surprisingly, interfacial crystal water molecules were calculated to contribute around 25% of the total calculated binding strength. Theoretical alanine mutations were completed by atomic deletions of the wild-type complexes. Strong correlations were observed between the calculated changes in binding free energy (deltadeltaG(calculated)) and the experimental values (deltadeltaG(observed)) for all but three of the 30 single residue mutations in the D1.3-HEL, D1.3-E5.2 and barnase-barstar systems and for all of the double mutations in the barnase-barstar system. This analysis finds that the observed differences in binding strength are consistent with a model that accounts for the changes in binding energy from the direct contacts between each member of the complex and indirect changes due to released crystallographic water molecules that are near the mutation site. The observed energy changes for double mutations in the barnase-barstar system is fully accounted for by considering water molecules bound jointly by each member of the complex.

Amino Acids↗
PubMed1996

Simulation of Contact Angle Hysteresis on Chemically Heterogeneous Surfaces

A quasi-steady-state simulation of contact angle hysteresis is presented. The model system consists of a two-dimensional drop on a smooth but chemically heterogeneous solid surface. The changes in the free energy of the system, the contact angle, and the size of the base of the drop are followed as its volume increases or decreases. The simulated contact angle hysteresis, including discontinuous changes in the contact angle and the size of the base of the drop, are shown to be very similar to typical experimental observations. In addition, the dependence of receding and advancing angles on the energy available for overcoming energy barriers is illustrated.

Journal Article↗
PubMedDate not supplied

Radiofrequency thermal effects on the human meniscus: an in vitro analysis.

PURPOSE: The purpose of this study was to evaluate the thermal effects produced in meniscal tissue with different radiofrequency (RF) energy levels and exposure times using a bipolar device. TYPE OF STUDY: An anatomic in vitro analysis of the thermal effects of an RF device. METHODS: A specially designed jig was used to apply RF energy under a constant force to cadaveric menisci. Three different energy levels were applied for 4 different contact times. RESULTS: The overall mean depth of thermal change was 547 microm (range, 468 to 650 microm). There were no significant differences or trends when contact time and energy were varied. CONCLUSIONS: These data suggest that increased contact times and energy outputs are not associated with increased thermal change in the meniscus. The submillimeter thermal denaturation was consistent with published reports using other thermal devices, such as laser.

Adult↗
PubMed1976

Behavioral and social effects of heroin self-administration and withdrawal.

Behavioral and social reactions to intravenously administered heroin were studied during a 33-day experimental addiction cycle. Three groups of four subject volunteers were allowed to self-administer heroin for a ten-day period as part of a longer study of oplate antagonists. Data relevant to sleep patterns, energy expenditure, social interaction, and other observable behaviors were collected during hourly observations. Comparison of behavioral differences before and after drug administration indicated few significant acute reactions. Reactions to long-term heroin self-administration were most pronounced in the areas of sleep behavior and social interaction. Subjects tended to sleep less, especially during the initial period of acquisition, and to withdraw more from social contact. No changes were noted in energy expenditure during waking hours. The results were interpreted in terms of physiological tolerance, central nervous system arousal, and sleep deprivation.

Adult↗
PubMed1983

Rabbit arterial endothelium and subendothelium. A change in interfacial free energy that may promote initial platelet adhesion.

Endothelial damage and exposure of the subendothelium is accompanied by platelet adhesion and aggregation. Thermodynamically, adhesion will occur if this process decreases the total free energy of the system. In this investigation, we have developed a contact angle technique to measure relative changes in the surface free energy of the arterial wall, before and after the endothelium has been removed. Sections of descending thoracic aorta from seven rabbits were tested with an equilibrium two-phase system of 4% polyethylene glycol (mol wt: 20,000)/4% dextran (mol wt: 2,000,000) in Hepes-buffered physiological saline. The tissue was split longitudinally, immersed in the polyethylene glycol phase, and test droplets of the denser dextran phase were placed on its surface. Advancing contact angles of the drop were measured from photomicrographs taken with polarizing optics. After testing, the endothelium was removed with a saline jet, which we had calibrated previously with scanning electron microscopy, and the tissue was retested. We measured angles of 86.0 +/- 1.1 degree (SEM), n = 64 for the intact endothelium and 20.0 +/- 0.8 degree (SEM), n = 61 on the subendothelial surface. Since the physical behavior of blood is probably similar to our polyethylene glycol bathing medium the subendothelium may also represent a surface of high interfacial free energy in vivo. Assuming that the surface energy of platelets is low, platelet adhesion to the subendothelium could reduce the total free energy of the system, by covering this high interfacial free energy surface.

Adsorption↗
PubMed2006

Changes in thermodynamic quantities upon contact of two solutes in solvent under isochoric and isobaric conditions.

The changes in excess thermodynamic quantities upon the contact of two solutes immersed in a solvent are analyzed using the radial-symmetric and three-dimensional versions of the integral equation theory. A simple model mimicking a solute in water is employed. The solute-solute interaction energy is not included in the calculations. Under the isochoric condition, the solute contact always leads to a positive entropy change irrespective of the solute solvophobicity or solvophilicity. The energy change is negative for solvophobic solutes while it is positive for solvophilic ones. Under the isobaric condition, the contact of solvophobic solutes results in system-volume compression but that of solvophilic ones gives rise to expansion. Effects of the compression and expansion on the changes in enthalpy and entropy are enlarged with rising temperature. When the solute solvophobicity is sufficiently high, the entropy change (multiplied by the absolute temperature) can become negative due to the compression, except at low temperatures with the result of an even larger, negative enthalpy change. The expansion in the case of solvophilic solutes leads to a large, positive entropy change accompanied by an even larger, positive enthalpy change. The changes in enthalpy and entropy are strongly dependent on the temperature. However, the changes in enthalpy and entropy are largely cancelled out and the temperature dependency of the free-energy change is much weaker. The authors also discuss possible relevance to the enthalpy-entropy compensation experimentally known for a variety of physicochemical processes in aqueous solution such as protein folding.

Journal Article↗
PubMed1982

The effects of videotape modeling and daily feedback on residential electricity conservation, home temperature and humidity, perceived comfort, and clothing worn: Winter and summer.

Two studies were conducted in all-electric townhouses and apartments in the winter (N = 83) and summer (N = 54) to ascertain how energy conservation strategies focusing on thermostat change and set-backs and other low-cost/no-cost approaches would affect overall electricity use and electricity used for heating and cooling, the home thermal environment, the perceived comfort of participants, and clothing that was worn. The studies assessed the effectiveness of videotape modeling programs that demonstrated these conservation strategies when used alone or combined with daily feedback on electricity use. In the winter, the results indicated that videotape modeling and/or feedback were effective relative to baseline and to a control group in reducing overall electricity use by about 15% and electricity used for heating by about 25%. Hygrothermographs, which accurately and continuously recorded temperature and humidity in the homes, indicated that participants were able to live with no reported loss in comfort and no change in attire at a mean temperature of about 62 degrees F when home and about 59 degrees F when asleep. The results were highly discrepant with prior laboratory studies indicating comfort at 75 degrees F with the insulation value of the clothing worn by participants in this study. In the summer, a combination of strategies designed to keep a home cool with minimal or no air conditioning, in conjunction with videotape modeling and/or daily feedback, resulted in overall electricity reductions of about 15% with reductions on electricity for cooling of about 34%, but with feedback, and feedback and modeling more effective than modeling alone. Despite these electricity savings, hygrothermograph recordings indicated minimal temperature change in the homes, with no change in perceived comfort or clothing worn. The results are discussed in terms of discrepancies with laboratory studies, optimal combinations of video-media and personal contact to promote behavior change, and energy policies that may be mislabeled as sacrificial and underestimate the effectiveness of conservation strategies such as those investigated in these studies.

Journal Article↗
PubMed1997

Nucleation and polymerization of sickle hemoglobin with Leu beta 88 substituted by Ala.

We have measured the solubility, and the rates of homogeneous and heterogeneous nucleation on sickle hemoglobin (HbS beta 6 Glu-->Val) additionally modified by site-directed mutagenesis to possess Ala rather than Leu at beta 88, which forms part of the receptor site for beta 6 Val in the sickle polymer. The solubility of the hemoglobin is increased at all temperatures, and is about 29 g/dl at 25 degrees C. Polymerization kinetics, induced by laser photolysis and observed by light-scattering intensity, showed exponential growth with rates about 300 times slower than experiments done on similar concentrations of HbS. When polymerization is carried out in small volumes, the time of measurable light-scattering signal to reach one-tenth of its final value (denoted as the tenth time) showed stochastic fluctuations, as is seen in pure HbS. Homogeneous nucleation rates were measured by observing distributions of tenth times and these rates were slowed by the mutation by almost 1000-fold relative to pure HbS. The kinetics, including the exponential progress curves and shape of the tenth time distributions, are well described by the double nucleation mechanism for polymerization. Analysis of the homogeneous nucleation rates leads to the surprising conclusion that the mutation has scarcely changed the energy of the intermolecular contacts despite the increase in solubility of the double mutant. This conclusion is supported by the stereochemistry of the modified contact site, in which the amount of exposed hydrophobic surface appears to be unchanged by the mutation. The increased solubility must therefore result from decreased motional freedom of molecules within the polymer, which could arise from tighter packing into the enlarged receptor pocket. This points up the ability of kinetic analysis to reveal important thermodynamic properties of assembly, and underlines the importance of the vibrational degrees of freedom in setting the final equilibrium constant. Chemical modifications to restrict vibrations and enhance the cost of polymerization may prove useful in constructing compounds to act as inhibitors of sickle cell gelation.

Binding Sites↗
PubMed1992

[Detection of mitochondrial contact sites and creatine kinase activity in Ca(2+)-stimulated rat hearts].

Contact sites are created by fusion of the inner and outer mitochondrial membrane. They represent a dynamic microcompartment for creatine kinase activity. In this microenvironment the active sites of creatine kinase, oxidative phosphorylation, and ADP/ATP transport interact during basal and stimulated metabolism. Electron microscopic studies showed that the occurrence rate of contact sites was changing according to the energy state of the mitochondrion (Biermans et al., 1989). The aim of this study was to stimulate the metabolism of the rat heart by extracellular calcium and to investigate the formation of contact sites and creatine kinase activity. Isolated rat hearts were perfused with Krebs-Henseleit solution containing 1.6 mmol Ca. After 15 min stabilization the hearts were subjected to 0.6, 0.9, 1.8, 2.2, 2.6, or 3.6 mmol Ca for a period of 15 min. Stimulation of the isolated rat hearts with increasing calcium concentrations was physiologically manifested by enhanced dp/dt and LVP values. A higher frequency rate of mitochondrial contact sites was observed and these were associated with higher creatine kinase activity. We suppose that induction of contact site formation is related to the functional activity of the Ca stimulated rat heart and thus efficient production and transport of energy is provided. (Tab. 1, Fig. 6, Ref. 18.).

Animals↗