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Nat Commun. 2014 Sep 10;5:4863. doi: 10.1038/ncomms5863.

Spontaneous transmembrane helix insertion thermodynamically mimics translocon-guided insertion.

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Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Massachusetts 21218, USA.
Institute of Natural Sciences and Department of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai 200240, China.
1] Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden [2] Science for Life Laboratory, Stockholm University, SE-17177 Solna, Sweden.
Institute of Structural and Molecular Biology, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.
Department of Physiology &Biophysics and the Center for Biomembrane Systems, University of California, Irvine, California 92697-4560, USA.


The favourable transfer free energy for a transmembrane (TM) α-helix between the aqueous phase and lipid bilayer underlies the stability of membrane proteins. However, the connection between the energetics and process of membrane protein assembly by the Sec61/SecY translocon complex in vivo is not clear. Here, we directly determine the partitioning free energies of a family of designed peptides using three independent approaches: an experimental microsomal Sec61 translocon assay, a biophysical (spectroscopic) characterization of peptide insertion into hydrated planar lipid bilayer arrays, and an unbiased atomic-detail equilibrium folding-partitioning molecular dynamics simulation. Remarkably, the measured free energies of insertion are quantitatively similar for all three approaches. The molecular dynamics simulations show that TM helix insertion involves equilibrium with the membrane interface, suggesting that the interface may play a role in translocon-guided insertion.

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