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Charge pattern matching as a 'fuzzy' mode of molecular recognition for the functional phase separations of intrinsically disordered proteins

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Charge pattern matching as a 'fuzzy' mode of molecular recognition for the functional phase separations of intrinsically disordered proteins
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Biologically functional liquid–liquid phase separation of intrinsically disordered proteins (IDPs) is driven by interactions encoded by their amino acid sequences. Little is currently known about the molecular recognition mechanisms for distributing different IDP sequences into various cellular membraneless compartments. Pertinent physics was addressed recently by applying random-phase-approximation (RPA) polymer theory to electrostatics, which is a major energetic component governing IDP phase properties. RPA accounts for charge patterns and thus has advantages over Flory–Huggins (FH) and Overbeek–Voorn mean-field theories. To make progress toward deciphering the phase behaviors of multiple IDP sequences, the RPA formulation for one IDP species plus solvent is hereby extended to treat polyampholyte solutions containing two IDP species plus solvent. The new formulation generally allows for binary coexistence of two phases, each containing a different set of volume fractions for the two different IDP sequences. The asymmetry between the two predicted coexisting phases with regard to their ratios for the two sequences increases with increasing mismatch between their charge patterns. This finding points to a multivalent, stochastic, 'fuzzy' mode of molecular recognition that helps populate various IDP sequences differentially into separate phase compartments. An intuitive illustration of this trend is provided by FH models, whereby a hypothetical case of ternary coexistence is also explored. Augmentations of the present RPA theory with a relative permittivity that depends on IDP volume fraction lead to higher propensities to phase separate, in line with the case with one IDP species we studied previously. Notably, the cooperative, phase-separation-enhancing effects predicted by the prescriptions for we deem physically plausible are much more prominent than that entailed by common effective medium approximations based on Maxwell Garnett and Bruggeman mixing formulas. Ramifications of our findings on further theoretical development for IDP phase separation are discussed.
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Transkript: Englisch(automatisch erzeugt)
Hello, this is a video abstract for our new Journal of Physics article. An emerging paradigm in cell biology states that a range of intracellular organelles are formed by liquid-liquid phase separation of proteins and or RNA.
These membraneless organelles have captivated biologists. Their complex phase behavior arising from interactions between the diverse protein sequences involved provides tantalizing opportunities for the development of theoretical frameworks to understand these biological systems.
We consider a three-component mixture including two different protein sequences plus water. The three components, depending on their volume ratios, can either form a homogeneous mixture or phase separate into phases alpha and beta. Both beta surrounded by alpha and vice versa are possible.
Here is a phase diagram to describe this process. First, we have a mixture of our two proteins. This will undergo phase separation to achieve a lower system-free energy yielding states alpha and beta. If two sequences have similar charge patterns, they are going to gather together and form a co-dilute and a co-condensed phase.
If the two sequences are very different, they exclude each other to form a sequence 1-reach and a sequence 2-reach phase. We use the random phase approximation theory to calculate phase diagrams. Here we plot two phase diagrams of different sequence pairs.
All original states inside the gray regions undergo phase separation into pairs of phases at the boundaries. We also investigate the three-phase or ternary phase separation using Flory-Hoggins model. In ternary phase separation, the final separated phases are fixed. All original states separate into the same final phases alpha, beta, and gamma.
The three final states define a triangle of ternary phase separation where all original states within this region will phase separate to the same three states. The three phases can be arranged in different ways, either one condensed phase surrounded by the other or two condensed phases individually.
Thank you. Hope you enjoy reading our paper.