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    Removable Backbone Modification Method for the Chemical Synthesis of Membrane Proteins
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    † School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
    ‡ Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
    *E-mail: [email protected]
    *E-mail: [email protected]
    *E-mail: [email protected]
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    Cite this: Acc. Chem. Res. 2017, 50, 5, 1143–1153
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    https://doi.org/10.1021/acs.accounts.7b00001
    Published April 4, 2017
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    Chemical synthesis can produce water-soluble globular proteins bearing specifically designed modifications. These synthetic molecules have been used to study the biological functions of proteins and to improve the pharmacological properties of protein drugs. However, the above advances notwithstanding, membrane proteins (MPs), which comprise 20–30% of all proteins in the proteomes of most eukaryotic cells, remain elusive with regard to chemical synthesis. This difficulty stems from the strong hydrophobic character of MPs, which can cause considerable handling issues during ligation, purification, and characterization steps. Considerable efforts have been made to improve the solubility of transmembrane peptides for chemical ligation. These methods can be classified into two main categories: the manipulation of external factors and chemical modification of the peptide. This Account summarizes our research advances in the development of chemical modification especially the two generations of removable backbone modification (RBM) strategy for the chemical synthesis of MPs.

    In the first RBM generation, we install a removable modification group at the backbone amide of Gly within the transmembrane peptides. In the second RBM generation, the RBM group can be installed into all primary amino acid residues. The second RBM strategy combines the activated intramolecular O-to-N acyl transfer reaction, in which a phenyl group remains unprotected during the coupling process, which can play a catalytic role to generate the activated phenyl ester to assist in the formation of amide. The key feature of the RBM group is its switchable stability in trifluoroacetic acid. The stability of these backbone amide N-modifications toward TFA can be modified by regulating the electronic effects of phenol groups. The free phenol group is acylated to survive the TFA deprotection step, while the acyl phenyl ester will be quantitatively hydrolyzed in a neutral aqueous solution, and the free phenol group increases the electron density of the benzene ring to make the RBM labile to TFA.

    The transmembrane peptide segment bearing RBM groups behaves like a water-soluble peptide during fluorenylmethyloxycarbonyl based solid-phase peptide synthesis (Fmoc SPPS), ligation, purification, and characterization. The quantitative removal of the RBM group can be performed to obtain full-length MPs. The RBM strategy was used to prepare the core transmembrane domain Kir5.1[64–179] not readily accessible by recombinant protein expression, the influenza A virus M2 proton channel with phosphorylation, the cation-specific ion channel p7 from the hepatitis C virus with site-specific NMR isotope labels, and so on. The RBM method enables the practical engineering of small- to medium-sized MPs or membrane protein domains to address fundamental questions in the biochemical, biophysical, and pharmaceutical sciences.

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    Cite this: Acc. Chem. Res. 2017, 50, 5, 1143–1153
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    https://doi.org/10.1021/acs.accounts.7b00001
    Published April 4, 2017
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