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PubMed2003

Roles of conformational stability and colloidal stability in the aggregation of recombinant human granulocyte colony-stimulating factor.

We studied the non-native aggregation of recombinant human granulocyte stimulating factor (rhGCSF) in solution conditions where native rhGCSF is both conformationally stable compared to its unfolded state and at concentrations well below its solubility limit. Aggregation of rhGCSF first involves the perturbation of its native structure to form a structurally expanded transition state, followed by assembly process to form an irreversible aggregate. The energy barriers of the two steps are reflected in the experimentally measured values of free energy of unfolding (DeltaG(unf)) and osmotic second virial coefficient (B(22)), respectively. Under solution conditions where rhGCSF conformational stability dominates (i.e., large DeltaG(unf) and negative B(22)), the first step is rate-limiting, and increasing DeltaG(unf) (e.g., by the addition of sucrose) decreases aggregation. In solutions where colloidal stability is high (i.e., large and positive B(22) values) the second step is rate-limiting, and solution conditions (e.g., low pH and low ionic strength) that increase repulsive interactions between protein molecules are effective at reducing aggregation. rhGCSF aggregation is thus controlled by both conformational stability and colloidal stability, and depending on the solution conditions, either could be rate-limiting.

Colloids↗
PubMed1981

Molecular stability of Hb Philly (alpha 2 beta 2 35(Cl) Tyr leads to Phe). Rhe relationship of hemoglobin stability to ligand state as defined by heat and mechanical shaking tests.

The molecular stability of Hb Philly (alpha 2 beta 2 35(Cl) Tyr leads to Phe) with different ligand states was compared with that of Hb A and Hb S using mechanical shaking and heat stability tests. The rates of mechanical denaturation of the oxy-forms of these hemoglobins decreased in the order of Hb S, Hb Philly, and Hb A, with relative ratios of 9.5: 5.6: 1.0. Upon oxidation to the met-forms, Hb Philly became mechanically most unstable, with ratios of 13.3: 23.0: 1.8, respectively. The deoxy-forms, of Hb A and Hb S were very stable, while that of Hb Philly was as unstable as the oxy-form. The addition of inositol hexaphosphate (IHP) to deoxy-Hb Philly stabilized the molecules. Since IHP restores the cooperative oxygen binding of Hp Philly, deoxy-Hb Philly appears to combine with IHP to change the quaternary structure required for cooperative oxygen binding and for stabilization of the molecule.

Drug Stability↗
PubMed1992

Stability and stabilization of fluorocarbon emulsions destined for injection.

The factors that have an impact on the stability, and the mechanisms of degradation of fluorocarbon emulsions suited for intravascular use, are briefly reviewed. Various ways of prolonging shelf stability are discussed. The effectiveness of perfluoroalkylated surfactants and/or co-surfactants as stabilizers is demonstrated. New means of stabilizing fluorocarbon-in-water emulsions using molecular dowels are presented.

Blood Substitutes↗
PubMed1981

[Stability testing of solid drugs using preferentially thin-layer chromatography and differential thermal analysis. Part 7: The stability of drugs and preparations (author's transl)].

Beside the temperature etc., certain properties of the crystal surface, the water content, catalytic actions and possible oxidation processes determine the stability of solids. Stability testing of drugs (aiming at fixing time-limits for the storage of drugs) according to the schedule elaborated by the authors provides specific quantitative methods of analysis only for substances of relatively poor storage stability. Already two or three temperature-time experiments (12h/140 degrees C; 20 d/90 degrees C; 43 d/80 degrees C) permit to evaluate the stability of the drugs by thin-layer chromatography and differential thermal analysis. Almost 80% of the substances tested comply with the prerequisites for the recommendation of a time-limit of 10 years for storage.

Catalysis↗
PubMedDate not supplied

Stability and stabilization of insulinotropin in a dextran formulation.

The stability of insulinotropin in a formulation containing 23% dextran-75 is studied. The effects of temperature, excipients, dextran concentration, and drug concentration on the stability of insulinotropin are examined. The tryptophan residue is identified as the primary degradation site in the insulinotropin molecule by LC-MS. Different antioxidants are used to stabilize the peptide. The combination of cysteine and EDTA is found to be most effective in stabilizing insulinotropin in the dextran formulation.

Buffers↗
PubMed2000

Lower kinetic limit to protein thermal stability: a proposal regarding protein stability in vivo and its relation with misfolding diseases.

In vitro thermal denaturation experiments suggest that, because of the possibility of irreversible alterations, thermodynamic stability (i.e., a positive value for the unfolding Gibbs energy) does not guarantee that a protein will remain in the native state during a given timescale. Furthermore, irreversible alterations are more likely to occur in vivo than in vitro because (a) some irreversible processes (e.g., aggregation, "undesirable" interactions with other macromolecular components, and proteolysis) are expected to be fast in the "crowded" cellular environment and (b) in many cases, the relevant timescale in vivo (probably related to the half-life for protein degradation) is expected to be longer than the timescale of the usual in vitro experiments (of the order of minutes). We propose, therefore, that many proteins (in particular, thermophilic proteins and "complex" proteins systems) are designed (by evolution) to have significant kinetic stability when confronted with the destabilizing effect of irreversible alterations. We show that, as long as these alterations occur mainly from non-native states (a Lumry-Eyring scenario), the required kinetic stability may be achieved through the design of a sufficiently high activation barrier for unfolding, which we define as the Gibbs energy barrier that separates the native state from the non-native ensemble (unfolded, partially folded, and misfolded states) in the following generalized Lumry-Eyring model: Native State <--> Non-Native Ensemble --> Irreversibly Denatured Protein. Finally, using familial amyloid polyneuropathy (FAP) as an illustrative example, we discuss the relation between stability and amyloid fibril formation in terms of the above viewpoint, which leads us to the two following tentative suggestions: (a) the hot spot defined by the FAP-associated amyloidogenic mutations of transthyretin reflects the structure of the transition state for unfolding and (b) substances that decrease the in vitro rate of transthyretin unfolding could also be inhibitors of amyloid fibril formation.

Amyloid Neuropathies↗
PubMed1992

End-stabilized microtubules observed in vitro: stability, subunit, interchange, and breakage.

We report a reliable method to prepare, in vitro, microtubules that are stabilized at both ends by axonemal structures, and report studies of their properties. Such "end-stabilized" microtubules neither grow nor shorten over times of several hours when tubulin subunits are present in the surrounding solution. When subunits are removed, the microtubules eventually break. Breakage occurs within a sinuous and flexible region, a few microns in length, that begins at a single point on the microtubule and grows. When breakage does occur, the resulting two free ends shorten very rapidly until the flexible part has depolymerized and the region of straight microtubule is reached. The remainder of the microtubule then shortens at rates comparable to those ordinarily observed in dynamic instability. Formation of the flexible region can be reversed if subunits are added to the buffer prior to breakage. End-stabilized microtubules are a useful tool for studying interactions of molecules with the microtubular wall. They may be a good model for interpreting stabilizing events that happen in the cell. A preliminary study of the effects of microtubule poisons on the wall is presented.

Alkaloids↗
PubMed2001

Dispersion Stability and Electrorheological Properties of Polyaniline Particle Suspensions Stabilized by Poly(vinyl methyl ether).

In the present article, a novel method of stabilization of a semi conductive polyaniline particle nonaqueous suspension of electrorheological (ER) materials was introduced. Using as the steric stabilizer poly(vinyl methyl ether) (PVME), a dispersion polymerization of aniline was performed and stable aqueous dispersions of the polyaniline were obtained. However, a stable colloidal suspension of polyaniline in silicone oil medium can be obtained only with a low concentration of PVME (0.75%), although the average size of the individual, redispersed particles in oil generally decreased with increasing concentration of PVME. At higher concentrations of PVME, formation of highly packed particle aggregates was investigated, as seen in the scanning electron microscopy images. The polyaniline suspension stabilized by 0.75% PVME content exhibited the best dispersing state and, therefore, showed the highest zero-field viscosity. Such a well-stabilized polyaniline suspension also showed the maximum ER property, namely the largest normalized yield stress in an electric field. Copyright 2001 Academic Press.

Journal Article↗
PubMed1998

A general rule for the relationship between hydrophobic effect and conformational stability of a protein: stability and structure of a series of hydrophobic mutants of human lysozyme.

To get a general rule for the relationship between hydrophobic effect and conformational stability, five Ile to Val and nine Val to Ala mutants (3SS mutants) from 3SS (C77A/C95A) human lysozyme were constructed. As known from previous studies, the 3SS protein lacking a disulfide bond between Cys77 and Cys95 is destabilized by enthalpic factors, as revealed by a decrease of about 20 kJ/mol in the denaturation Gibbs energy change (DeltaG) value, as compared to the wild-type protein, which has four disulfide bonds. In this study, the stabilities and structures of the 3SS mutants were determined by differential scanning calorimetry and X-ray crystal analysis, respectively, and compared with those of the mutants (4SS mutants) from the wild-type (4SS) protein published previously. The stabilities of all the 3SS mutants, except for V110A-3SS were decreased as compared with that of the 3SS protein, coinciding with the results for the 4SS mutants. The change in the denaturation Gibbs energy change (DeltaDeltaG) values of the 3SS mutants relative to the 3SS protein at the denaturation temperature (49.2 degreesC) of the 3SS protein at pH 2.7 were similar to those of the equivalent 4SS mutants relative to the wild-type at 64.9 degreesC. The Delta DeltaG values of the 3SS mutants correlated with the changes in hydrophobic surface area exposed upon denaturation (Delta DeltaASAHP) for all of the hydrophobic residues when the effects of the secondary structure propensity were considered. This correlation is identical with that previously found for the 4SS mutants. The linear relation between Delta DeltaG and Delta DeltaASAHP for all of the hydrophobic residues with the same slope was found also for the mutants of T4 lysozyme already reported, indicating that this is a general relationship between changes in conformational stability and changes in ASA values of hydrophobic residues due to mutations.

Calorimetry↗
PubMed1999

Calorimetric analysis of the Ca(2+)-binding betagamma-crystallin homolog protein S from Myxococcus xanthus: intrinsic stability and mutual stabilization of domains.

The betagamma-crystallin superfamily consists of a class of homologous two-domain proteins with Greek-key fold. Protein S, a Ca(2+)-binding spore-coat protein from the soil bacterium Myxococcus xanthus exhibits a high degree of sequential and structural homology with gammaB-crystallin from the vertebrate eye lens. In contrast to gammaB-crystallin, which undergoes irreversible aggregation upon thermal unfolding, protein S folds reversibly and may therefore serve as a model in the investigation of the thermodynamic stability of the eye-lens crystallins. The thermal denaturation of recombinant protein S (PS) and its isolated domains was studied by differential scanning calorimetry in the absence and in the presence of Ca(2+) at varying pH. Ca(2+)-binding leads to a stabilization of PS and its domains and increases the cooperativity of their equilibrium unfolding transitions. The isolated N-terminal and C-terminal domains (NPS and CPS) obey the two-state model, independent of the pH and Ca(2+)-binding; in the case of PS, under all conditions, an equilibrium intermediate is populated. The first transition of PS may be assigned to the denaturation of the C-terminal domain and the loss of domain interactions, whereas the second one coincides with the denaturation of the isolated N-terminal domain. At pH 7.0, in the presence of Ca(2+), where PS exhibits maximal stability, the domain interactions at 20 degrees C contribute 20 kJ/mol to the overall stability of the intact protein.

Bacterial Proteins↗
PubMed1988

Effects of crosslinking on the thermal stability of hemoglobins. II. The stabilization of met-, cyanomet-, and carbonmonoxyhemoglobins A and S with bis(3,5-dibromosalicyl) fumarate.

Hemoglobins A and S were crosslinked between Lys 82 beta 1 and Lys 82 beta 2 using bis (3,5-dibromosalicyl) fumarate (J. A. Walder et al. (1979) Biochemistry 18, 4265). Thermal denaturation experiments were used to compare the stabilities of the met, cyanomet, and carbonmonoxy forms of these crosslinked hemoglobins to the corresponding uncrosslinked proteins. Uncrosslinked carbonmonoxy- and cyanomethemoglobins had transition temperatures about 11 degrees C higher than the corresponding met samples. The increase in denaturation temperature (Tm) due to crosslinking was 15 degrees C for the methemoglobins, 10 degrees C for the cyanomethemoglobins, and 4 degrees C for the carbonmonoxy ones. There was no significant difference in stability between the met and carbonmonoxy crosslinked proteins. In order of increasing stability the samples were: met Hb S less than met Hb A less than CO Hb S less than CO Hb A = CN-met Hb A less than met XL-Hb S = CO XL-Hb S less than met XL-Hb A = CO XL-Hb A less than CN-met XL-Hb A. The slight decrease in the stability of Hb S (beta 6 Glu----Val) compared to Hb A can be explained by the replacement of an external ionic group by a hydrophobic residue in Hb S. In mixtures of crosslinked and normal Hb A, the Tm of the uncrosslinked material was slightly increased by the presence of the more stable crosslinked hemoglobin. The effects of both crosslinking and cyanide or carbon monoxide binding can be explained by Le Chatelier's principle since both would favor the native form of the protein.

Aspirin↗
PubMed1993

Stabilization of microtubules by dynein-binding in vitro. Stability of microtubule-dynein complex.

We have studied the effects of dynein binding on the stability of microtubules in vitro, using Tetrahymena ciliary dynein and microtubules (three-cycled purified microtubules: 3 X-Mts and phosphocellulose-column purified microtubules: PC-Mts). To determine the relative stability of the microtubules, we first prepared the microtubules bound with dynein (Mts--dynein complex) and subjected the Mts-dynein complex to treatments that depolymerize the microtubules, such as dilution to below critical concentration of tubulin, calcium ions and lower temperature. Dark-field microscopy revealed that the microtubules in the Mts--dynein complex appeared intact under conditions which otherwise result in microtubule depolymerization. However, when dynein was dissociated from the Mts--dynein complex with addition of ATP, no microtubule was found in the specimens under the same conditions. That is, the microtubules in the Mts--dynein complex did not depolymerize upon dilution with the buffer solution to below critical concentration of tubulin. However, addition of ATP to the diluted specimen caused dynein to become separated from the Mts, resulting in complete depolymerization of the microtubules. Stability of the microtubules was also studied by the turbidity changes and was confirmed by the patterns of stained gel bands in electrophoresis. With the addition of calcium ion, the Mts--dynein complex decomposed into separate molecules dynein and tubulin. At the lower temperature of 0 degrees C, the 3 X-Mts--dynein complex was decomposed into dynein and tubulin, while the microtubules in the PC-Mts--dynein complex did not depolymerize. Although we have not yet studied the effects of cytoplasmic dynein binding on the microtubules, the results suggest that the stabilizing effect of dynein binding to the microtubules is one of the important functions of dynein in vivo.

Animals↗
PubMed2006

Error propagation across levels of organization: from chemical stability of ribosomal RNA to developmental stability.

My hypothesis integrates molecular and whole-organism levels of development. A physico-chemical property of nucleotides (their dipole moment), confers structural thermostability on double-stranded sequences, and decreases chemical stability of single-stranded sequences. According to this approach, low ribosomal RNA stability should decrease the precision of protein synthesis and whole-organism developmental stability. Indeed, substitution frequencies in pseudogenes are proportional to the subtraction of the dipole moment of the substituting nucleotide from that of the substituted one, and developmental instability, estimated by morphological fluctuating asymmetry (FA), correlates with mammal 12s rRNA base content of loop (but not stem) regions. In lizards, fit to the single-strand rationale of sequence chemical stability decreases with the level of poikilothermy of the investigated lizard family, suggesting interactions between changes in body temperature, ribosomal structure and developmental instability. Results confirm the hypothesis (less than for 12s rRNA) in: third codon positions of cytochrome B, probably because, unlike rRNAs, specific mRNAs affect only the protein they code; and 16s rRNA, apparently because its base composition is more affected by genome-wide mutational biases than that of 12s rRNA.

Animals↗
PubMed2004

Evaluation of the tear film stability after laser in situ keratomileusis using the tear film stability analysis system.

PURPOSE: To evaluate the tear film stability of patients before and after laser in situ keratomileusis (LASIK) using the tear film stability analysis system (TSAS). DESIGN: Prospective observational case series. METHODS: New videokeratography software for a topographic modeling system (TMS-2N) was developed that can automatically capture consecutive corneal surface images every second for 10 seconds. Thirty-four subjects (64 eyes) who underwent myopia LASIK were enrolled in this study. All subjects were examined with the new system before LASIK and at 1 week, 1 month, 3 months, and 6 months after the surgery. Corneal topographs were analyzed for tear breakup time (TMS breakup time) and breakup area (TMS breakup area). Based on pre-LASIK TSAS analysis, subjects were separated into normal and abnormal TSAS value groups. The criteria for the normal group were either TMS breakup time more than 5 seconds or TMS breakup area less than 0.2. The percentage of the occurrence of superficial punctuate keratitis was compared between the two groups with regard to subject's dry eye signs and symptoms. RESULTS: Tear film stability decreased significantly during the early period after LASIK, as indexed by decreased TMS breakup time and increased TMS breakup area. Tear film instability resolved at 6 months after surgery. Before LASIK, 22 subjects (43 eyes) had normal TSAS evaluation and 12 subjects (21 eyes) were abnormal. After LASIK, among normal TSAS value eyes, 8 of 43 (18.6%) eyes developed superficial punctuate keratitis. In sharp contrast, 14 of 21 (66.7%) eyes in the abnormal group displayed superficial punctuate keratitis, correlating well with the patients' dry eye symptoms. The difference in the presence of superficial punctuate keratitis after LASIK between normal and abnormal TSAS value groups was statistically significant (P <.001). Subjects with abnormal TSAS evaluation also displayed resistance to dry eye treatment and had extended period of recovery. CONCLUSIONS: Tear film stability analysis can be a useful means for screening LASIK candidates before surgery and for prognosticating dry eye symptoms thereafter.

Adult↗
PubMed2001

Does body stability depend on postural chain mobility or stability area?

The purpose of this study was to examine whether postural stability depends only on the support base perimeter, that is the stability area, when body balance is perturbed by respiration. To this end, seven normal subjects were asked to breathe quietly, breathe deeply and to hold their breath (apnoea). They were asked to maintain a standing posture (Sta), and two sitting postures differing by the ischio femoral contact with the seat (Sit100 and Sit30). In other words, these three postures differed not only by the stability area, but also by pelvis mobility. The thoracic perimeter, displacement of the centre of pressure (CP) and iliac crest acceleration (Ah), taken as an index of pelvis mobility, of seven normal subjects were recorded. The results showed that the sway path (SP) was longer in seated subjects than in standing ones, and in Sit100 than in Sit30. The distance between the CP extreme positions (Delta Xp) varied in the opposite direction to SP. Iliac crests and thoracic displacements were shown to be in phase in Sit condition, and did not display any particular pattern in Sta. It was concluded that postural steadiness depends on the postural chain mobility in addition to stability area. As pelvis and lumbar column mobility are related, it is proposed that both contribute to postural chain mobility, owing to respiratory perturbation being compensated.

Abdomen↗
PubMed2006

Foam films stabilized with dodecyl maltoside. 2. Film stability and gas permeability.

The gas permeability and stability of foam films stabilized by n-dodecyl-beta-D-maltoside (beta-C(12)G(2)) were determined. The permeability coefficient (K, cm/s) and the mean film lifetime were measured as a function of the surfactant concentration. The films are less permeable than those stabilized by other surfactants at comparable conditions. The permeability coefficient decreases with increasing surfactant concentration. It does not show a remarkable dependence on the salt concentration. Stable Newton black foam films (NBFs) are formed above a surfactant concentration of 3.9 x 10(-)(6) M beta-C(12)G(2) in the presence of 0.2 M NaCl. The theory of nucleation hole formation in NBFs was applied to describe the observed dependencies of the permeability and film stability on the surfactant concentration. The theory gave satisfactory relation to the experiment.

Detergents↗
PubMed1998

Helix stabilizing factors and stabilization of thermophilic proteins: an X-ray based study.

We have compared the X-ray structures of 13 thermophilic proteins with their mesophilic homologues, in order to bring out differences in the stability of helices. The energy terms of a helix-coil transition algorithm were used to evaluate helix stability. Helices of thermophilic proteins are more stable than the mesophilic homologues in 69% of cases. This is due mainly to intrinsic helical propensities of amino acids, whereas minor effects are linked to main chain H-bonds, side chain-side chain interactions, capping motifs and charge-dipole effects. Furthermore, the frequency of 10 helix stabilizing factors recognized by appropriate sequence patterns was evaluated. The only factor occurring significantly in the thermostable proteins was the lack of beta branched residues. Other factors do not show a definite trend, although their occurrence in proteins is believed to be important for stability. This is discussed in the light of protein engineering applications.

Animals↗
PubMed1998

Stabilization of Aspergillus awamori glucoamylase by proline substitution and combining stabilizing mutations.

To stabilize Aspergillus awamori glucoamylase (GA), three proline substitution mutations were constructed. When expressed in Saccharomyces cerevisiae, Ser30-->Pro (S30P) stabilized the enzyme without decreased activity, whereas Asp345-->Pro (D345P) did not significantly alter and Glu408-->Pro (E408P) greatly decreased enzyme thermostability. The S30P mutation was combined with two previously identified stabilizing mutations: Gly137-->Ala, and Asn20-->Cys/Ala27-->Cys (which creates a disulfide bond between positions 20 and 27). The combined mutants demonstrated cumulative stabilization as shown by decreased irreversible thermoinactivation rates between 65 and 80 degrees C. Additionally, two of the combined mutants outperformed wild-type GA in high-temperature (65 degrees C) saccharifications of DE 10 maltodextrin and were more active than the wild-type enzyme when assayed using maltose as substrate.

Amino Acid Substitution↗