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Ion-activated attractive patches as a mechanism for controlled protein interactions

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ABSTRACT

The understanding of protein interactions to control phase and nucleation behavior of protein solutions is an important challenge for soft matter, biological and medical research. Here, we present ion bridges of multivalent cations between proteins as an ion-activated mechanism for patchy interaction that is directly supported by experimental findings in protein crystals. A deep understanding of experimentally observed phenomena in protein solutions—including charge reversal, reentrant condensation, metastable liquid-liquid phase separation, cluster formation and different pathways of crystallization—is gained by an analytic model that directly displays parameter dependencies and physical connections. The direct connection between experiment and theory provides a conceptual framework for future experimental, computational and theoretical research on topics such as rational design of phase behavior and crystallization pathways on the basis of the statistical physics of patchy particles.

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(A): The cluster size distribution  broadens with increasing bond probability (blue lines: pb = 0.0001, 0.001, 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3; red line: ), implying the growth of larger clusters, in particular when approaching the percolation limit . (B): The integrated scattering power of all clusters, normalized to the monomer solution, shows a steep increase at intermediate chemical potentials μs, i.e. intermediate salt concentrations. This behavior represents one reason for the turbidity in the solution during the reentrant condensation. (C): Another reason for turbidity is opalescence close to the LLPS boundary and the LLPS itself. The forward scattering intensity is proportional to the isothermal compressibility , normalized to the hard sphere value, that outlines the reentrant effect. The calculations in B, C are performed for three volume fractions below, through and above the LLPS.
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f3: (A): The cluster size distribution broadens with increasing bond probability (blue lines: pb = 0.0001, 0.001, 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3; red line: ), implying the growth of larger clusters, in particular when approaching the percolation limit . (B): The integrated scattering power of all clusters, normalized to the monomer solution, shows a steep increase at intermediate chemical potentials μs, i.e. intermediate salt concentrations. This behavior represents one reason for the turbidity in the solution during the reentrant condensation. (C): Another reason for turbidity is opalescence close to the LLPS boundary and the LLPS itself. The forward scattering intensity is proportional to the isothermal compressibility , normalized to the hard sphere value, that outlines the reentrant effect. The calculations in B, C are performed for three volume fractions below, through and above the LLPS.

Mentions: A natural consequence of the ion bridges is the formation of clusters throughout the entire phase diagram (Fig. 2B). Using the Flory-Stockmeyer theory4344 the number density ρn of n-clusters and the number fraction Φ of proteins in clusters are given by With increasing average ion-bridge probability pb, which is provided by the Wertheim theory1 (see Methods), larger cluster become more frequent (Fig. 3A). Thus, with increasing pb, protein diffusion is expected to be reduced substantially due to cluster formation, as indeed observed in recent experiments45. Once pb exceeds the percolation value , a system-spanning cluster can form, implying that dynamics in the solution is severely slowed down or even arrested.


Ion-activated attractive patches as a mechanism for controlled protein interactions
(A): The cluster size distribution  broadens with increasing bond probability (blue lines: pb = 0.0001, 0.001, 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3; red line: ), implying the growth of larger clusters, in particular when approaching the percolation limit . (B): The integrated scattering power of all clusters, normalized to the monomer solution, shows a steep increase at intermediate chemical potentials μs, i.e. intermediate salt concentrations. This behavior represents one reason for the turbidity in the solution during the reentrant condensation. (C): Another reason for turbidity is opalescence close to the LLPS boundary and the LLPS itself. The forward scattering intensity is proportional to the isothermal compressibility , normalized to the hard sphere value, that outlines the reentrant effect. The calculations in B, C are performed for three volume fractions below, through and above the LLPS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382698&req=5

f3: (A): The cluster size distribution broadens with increasing bond probability (blue lines: pb = 0.0001, 0.001, 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3; red line: ), implying the growth of larger clusters, in particular when approaching the percolation limit . (B): The integrated scattering power of all clusters, normalized to the monomer solution, shows a steep increase at intermediate chemical potentials μs, i.e. intermediate salt concentrations. This behavior represents one reason for the turbidity in the solution during the reentrant condensation. (C): Another reason for turbidity is opalescence close to the LLPS boundary and the LLPS itself. The forward scattering intensity is proportional to the isothermal compressibility , normalized to the hard sphere value, that outlines the reentrant effect. The calculations in B, C are performed for three volume fractions below, through and above the LLPS.
Mentions: A natural consequence of the ion bridges is the formation of clusters throughout the entire phase diagram (Fig. 2B). Using the Flory-Stockmeyer theory4344 the number density ρn of n-clusters and the number fraction Φ of proteins in clusters are given by With increasing average ion-bridge probability pb, which is provided by the Wertheim theory1 (see Methods), larger cluster become more frequent (Fig. 3A). Thus, with increasing pb, protein diffusion is expected to be reduced substantially due to cluster formation, as indeed observed in recent experiments45. Once pb exceeds the percolation value , a system-spanning cluster can form, implying that dynamics in the solution is severely slowed down or even arrested.

View Article: PubMed Central - PubMed

ABSTRACT

The understanding of protein interactions to control phase and nucleation behavior of protein solutions is an important challenge for soft matter, biological and medical research. Here, we present ion bridges of multivalent cations between proteins as an ion-activated mechanism for patchy interaction that is directly supported by experimental findings in protein crystals. A deep understanding of experimentally observed phenomena in protein solutions—including charge reversal, reentrant condensation, metastable liquid-liquid phase separation, cluster formation and different pathways of crystallization—is gained by an analytic model that directly displays parameter dependencies and physical connections. The direct connection between experiment and theory provides a conceptual framework for future experimental, computational and theoretical research on topics such as rational design of phase behavior and crystallization pathways on the basis of the statistical physics of patchy particles.

No MeSH data available.


Related in: MedlinePlus