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Synthesis and Evaluation of a Library of Alternating Amphipathic Copolymers to Solubilize and Study Membrane Proteins.

ABSTRACT: Amphipathic copolymers such as poly(styrene-maleic acid) (SMA) are promising tools for the facile extraction of membrane proteins (MPs) into native nanodiscs. Here, we designed and synthesized a library of well-defined alternating copolymers of SMA analogues in order to elucidate polymer properties that are important for MP solubilization and stability. MP extraction efficiency was determined using KcsA from E. coli membranes, and general solubilization efficiency was investigated via turbidimetry experiments on membranes of E. coli, yeast mitochondria, and synthetic lipids. Remarkably, halogenation of SMA copolymers dramatically improved solubilization efficiency in all systems, while substituents on the copolymer backbone improved resistance to Ca²⁺. Relevant polymer properties were found to include hydrophobic balance, size and positioning of substituents, rigidity, and electronic effects. The library thus contributes to the rational design of copolymers for the study of MPs.

SUBMITTER: Kopf AH

PROVIDER: S-EPMC8924871 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Synthesis and Evaluation of a Library of Alternating Amphipathic Copolymers to Solubilize and Study Membrane Proteins.

Kopf Adrian H AH Lijding Odette O Elenbaas Barend O W BOW Koorengevel Martijn C MC Dobruchowska Justyna M JM van Walree Cornelis A CA Killian J Antoinette JA

Biomacromolecules 20220107 3

Amphipathic copolymers such as poly(styrene-maleic acid) (SMA) are promising tools for the facile extraction of membrane proteins (MPs) into native nanodiscs. Here, we designed and synthesized a library of well-defined alternating copolymers of SMA analogues in order to elucidate polymer properties that are important for MP solubilization and stability. MP extraction efficiency was determined using KcsA from <i>E. coli</i> membranes, and general solubilization efficiency was investigated via tur ...[more]

PMID: 34994549

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Project description:Investigation of complex molecular systems depends on our ability to correlate physical measurements with molecular structure. Interpretation of studies that rely on synthetic polymers is generally limited by their heterogeneity; i.e., there is variation in the number and arrangement of the monomeric building blocks that have been incorporated. Superior physics and biology can be performed with materials and tools that exert precise control over the sequence and spacing of functional groups. An interest in functional ligands combined with a desire to control the orientation and stereochemistry of monomer incorporation led to the design of new substrates for ruthenium-catalyzed ring-opening metathesis polymerization (ROMP). We discovered that ROMP of cyclobutene-1-carboxamides provides uniform and translationally invariant polymers. In contrast, cyclobutene-1-carboxylate esters ring open upon treatment with ruthenium catalyst, but they are stable to homopolymerization. However, in the presence of cyclohexene monomers, they undergo alternating ROMP (AROMP or alt-ROMP) to give copolymers with a precisely controlled sequence. The alternating cyclobutene ester/cyclohexene pair provides access to functional group spacing larger than is possible with homopolymers. This can be desirable; for example, polymers with a regular 8-10 Å backbone spacing of cationic charge and with between four and eight cationic groups were the most effective antibacterial agents and had low cytotoxicity. Moreover, the AROMP chemistry allows alternation of two functional moieties: one associated with the cyclohexene and one attached to the cyclobutene. In the case of antibacterial copolymers, the alternating chemistry allowed variation of hydrophobicity via the cyclohexene while maintaining a constant cation spacing through the cyclobutene. In the case of copolymers that bear donor and acceptor groups, strict alternation of the groups increased intrachain charge transfer. Like cyclobutene-1-carboxylate esters, bicyclo[4.2.0]oct-7-ene-7-carboxylate esters ring open upon treatment with ruthenium catalyst and undergo ring opening cross-metathesis with cyclohexene to form alternating copolymers. The corresponding bicyclo[4.2.0]oct-7-ene-7-carboxyamides isomerize to the bicyclo[4.2.0]oct-1(8)-ene-8-carboxamides before they can ring open. However, the isomerized amides undergo ruthenium-catalyzed ring opening metathesis and rapidly AROMP with cyclohexene. Our alternating copolymer systems allow functionality to be placed along a polymer chain with larger than typical spacing. We have used both homopolymers and alternating copolymers for defining the functional group density required for targeting a cell surface and for the exploration of functional group positioning within a polymer chain. These polymer systems provide access to new materials with previously inaccessible types of nanoscale structures.

Dataset Information

Synthesis and Evaluation of a Library of Alternating Amphipathic Copolymers to Solubilize and Study Membrane Proteins.

Publications

Synthesis and Evaluation of a Library of Alternating Amphipathic Copolymers to Solubilize and Study Membrane Proteins.

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