Dataset Information

Protein aggregation in salt solutions.

ABSTRACT: Protein aggregation is broadly important in diseases and in formulations of biological drugs. Here, we develop a theoretical model for reversible protein-protein aggregation in salt solutions. We treat proteins as hard spheres having square-well-energy binding sites, using Wertheim's thermodynamic perturbation theory. The necessary condition required for such modeling to be realistic is that proteins in solution during the experiment remain in their compact form. Within this limitation our model gives accurate liquid-liquid coexistence curves for lysozyme and ? IIIa-crystallin solutions in respective buffers. It provides good fits to the cloud-point curves of lysozyme in buffer-salt mixtures as a function of the type and concentration of salt. It than predicts full coexistence curves, osmotic compressibilities, and second virial coefficients under such conditions. This treatment may also be relevant to protein crystallization.

SUBMITTER: Kastelic M

PROVIDER: S-EPMC4450416 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Protein aggregation in salt solutions.

Kastelic Miha M Kalyuzhnyi Yurij V YV Hribar-Lee Barbara B Dill Ken A KA Vlachy Vojko V

Proceedings of the National Academy of Sciences of the United States of America 20150511 21

Protein aggregation is broadly important in diseases and in formulations of biological drugs. Here, we develop a theoretical model for reversible protein-protein aggregation in salt solutions. We treat proteins as hard spheres having square-well-energy binding sites, using Wertheim's thermodynamic perturbation theory. The necessary condition required for such modeling to be realistic is that proteins in solution during the experiment remain in their compact form. Within this limitation our model ...[more]

PMID: 25964322

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Project description:BACKGROUND:Oral rehydration solution (ORS) is used to treat the dehydration caused by diarrhoeal diseases, including cholera. ORS formulations with an osmolarity (a measure of solute concentration) of ? 270 mOsm/L (ORS ? 270) are safe and more effective than ORS formulations with an osmolarity of ? 310 mOsm/L (ORS ? 310) for treating non-cholera diarrhoea. As cholera causes rapid electrolyte loss, it is important to know if these benefits are similar for people suffering from cholera. OBJECTIVES:To compare the safety and efficacy of ORS ?270 with ORS ? 310 for treating dehydration due to cholera. SEARCH METHODS:We searched the Cochrane Infectious Disease Group Specialized Register (April 2011), CENTRAL (The Cochrane Library Issue 4, 2011), MEDLINE (1966 to April 2011), EMBASE (1974 to April 2011), and LILACS (1982 to April 2011). We also contacted organizations and searched reference lists. SELECTION CRITERIA:Randomized controlled trials comparing ORS ? 270 with ORS ? 310 for treating adults and children with acute diarrhoea due to cholera. DATA COLLECTION AND ANALYSIS:Two reviewers independently applied eligibility criteria, assessed trial quality, and extracted data. We pooled dichotomous data using risk ratio (RR), pooled continuous data using mean difference (MD) or the standardized mean difference (SMD), and presented the results with 95% confidence intervals (CI). MAIN RESULTS:For glucose-based ORS, seven trials (718 participants) met the inclusion criteria. Biochemical hyponatraemia (blood sodium levels < 130 mmol/L) was more common with ORS ? 270 (RR 1.67, CI 1.09 to 2.57; 465 participants, four trials), while a higher level of severe biochemical hyponatraemia (blood sodium levels < 125 mmol/L) in the same group was not significant (RR 1.58, CI 0.62 to 4.04; 465 participants, four trials). No instances of symptomatic hyponatraemia or death were noted in the trials that intended to record them. We found no statistically significant difference in the need for unscheduled intravenous infusion. Analyses separating children and adults showed no obvious trends.Two trials also examined rice-based ORS. In the ORS ? 270 group, duration of diarrhoea was shorter (MD -11.42 hours, CI -13.80 to -9.04; 102 participants, two trials). AUTHORS' CONCLUSIONS:In people with cholera, ORS ? 270 is associated with biochemical hyponatraemia when compared with ORS ? 310, but there are no differences in terms of other outcomes. Although this risk does not appear to be associated with any serious consequences, the total patient experience in existing trials is small. Under wider practice conditions, especially where patient monitoring is difficult, caution is warranted.

Project description:Protein aggregation in vivo has been extensively associated with a large spectrum of human diseases. On the other hand, mechanistic insights into protein aggregation in vitro were incomplete due to the inability in solubilizing insoluble proteins for high-resolution biophysical investigations. However, a new avenue may be opened up by our recent discovery that previously-thought insoluble proteins can in fact be solubilized in salt-free water. Here we use this approach to study the NMR structural and dynamic properties of an insoluble SH3 mutant with a naturally-occurring insertion of Val22 at the tip of the diverging turn. The obtained results reveal: 1) regardless of whether the residue is Val, Ala, Asp or Arg, the insertion will render the first hNck2 SH3 domain to be insoluble in buffers. Nevertheless, all four mutants could be solubilized in salt-free water and appear to be largely unfolded as evident from their CD and NMR HSQC spectra. 2) Comparison of the chemical shift deviations reveals that while in V22-SH3 the second helical region is similarly populated as in the wild-type SH3 at pH 2.0, the first helical region is largely unformed. 3) In V22-SH3, many non-native medium-range NOEs manifest to define non-native helical conformations. In the meanwhile a small group of native-like long-range NOEs still persists, indicating the existence of a rudimentary native-like tertiary topology. 4) Although overall, V22-SH3 has significantly increased backbone motions on the ps-ns time scale, some regions still own restricted backbone motions as revealed by analyzing (15)N relaxation data. Our study not only leads to the establishment of the first high-resolution structural and dynamic picture for an insoluble protein, but also shed more light on the molecular events for the nonhierarchical folding mechanism. Furthermore, a general mechanism is also proposed for in vivo protein aggregation triggered by the genetic mutation and posttranslational modification.

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Protein aggregation in salt solutions.

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Protein aggregation in salt solutions.

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