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We present a general theory of the phase behavior of concentrated multicomponent solutions of charged flexible heteropolymers with specific chemical sequences. Using a field theoretic formalism, we have accounted for sequence specificity, electrostatic and van der Waals interactions among all constituent species, and topological correlations among all heteropolymer chains in the system. Our general expression for the Helmholtz free energy of the system is in terms of density profiles of the various components and is an explicit function of the sequence specificity of the heteropolymers, polymer concentration, salt concentration, chemical mismatch among the various monomers and solvent, and temperature. We illustrate our general theory in the context of the self-assembly of intrinsically disordered proteins by considering solutions of sequence-specific charged-neutral heteropolymers. For the heteropolymers under consideration, the system exhibits microphase separation. The boundaries of order–disorder transition and the relative stabilities of the canonical microphase-separated morphologies (lamellar, cylindrical, and spherical) are presented in the weak segregation limit as functions of sequence, polymer concentration, chemical mismatch parameters, and salt concentration. Unique mapping between heteropolymer sequence and morphology diagram is presented. The derived general theory is of broad applicability in addressing sequence effects on the thermodynamic behavior of any multicomponent system containing flexible heteropolymers.
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Microstructural Organization in α-Synuclein Solutions
We have investigated the structural evolution in solutions of the intrinsically disordered protein, α-synuclein, as a function of protein concentration and added salt concentration. Accounting for electrostatic and excluded volume interactions based on the protein sequence, our Langevin dynamics simulations reveal that α-synuclein molecules assemble into aggregates and percolated structures with a spontaneous selection of a dominant structure characteristic of microphase separation. This microphase assembly is mainly driven by electrostatic interactions between the residues in N-terminal and C-terminal of the protein molecules, and presence of salt loosens the compactness of the microstructures. We have quantified the features of the spontaneously formed microstructures using interchain radial distribution functions, and experimentally measurable inter-residue contact maps and static structure factors. Our results are in contrast to the commonly hypothesized mechanism of liquid–liquid phase separation (LLPS) for the formation of droplets in solutions of intrinsically disordered proteins, opening a new paradigm to understand the birth and structure of membraneless organelles. In general, construction of phase diagrams of intrinsically disordered proteins and other biomacromolecular systems needs to incorporate features of microphase separation into other mechanisms of macrophase separation and percolation.
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- Award ID(s):
- 2015935
- PAR ID:
- 10498938
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- Macromolecules
- Volume:
- 55
- Issue:
- 11
- ISSN:
- 0024-9297
- Page Range / eLocation ID:
- 4228 to 4236
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acs.macromol.1c02550
