Protein design has significantly advanced to allow incorporation of desired artificial features to protein structure, assembly and function, yielding rich understanding in how structure relates to function. However, similar investigations with transmembrane proteins are extremely rare due to limited knowledge and technical challenges. Here, we present computational design of a transmembrane helix that self-assembles into a stable three-dimensional structure capable of generating conformational dynamics linked to co-transportation function. De-novo minimalist transporter features dual-subunit topology consisting a 25-residue-long anti-parallel homo-tetrameric bundle that uses proton gradient to drive Zn(II) up its gradient across the bilayer of lipid vesicles, indicated by solids NMR, solution NMR, molecular dynamics simulations and functional assay. Together with its subunit's crystal structures, the first for designed transmembrane domain, our data and simulations critically corroborate the mechanistic importance of structural inter-conversion proposed in alternating access theory for transporters and support gene-duplication proposed for evolution of their dual topology.

Computational design of metallotransporter

248th National Meeting (2014)

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