Energy landscape underlying spontaneous insertion and folding of an alpha-helical transmembrane protein into a bilayer

Wei Lu, Nicholas P. Schafer and Peter G. Wolynes ()
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Wei Lu: Rice University
Nicholas P. Schafer: Rice University
Peter G. Wolynes: Rice University

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Membrane protein folding mechanisms and rates are notoriously hard to determine. A recent force spectroscopy study of the folding of an α-helical membrane protein, GlpG, showed that the folded state has a very high kinetic stability and a relatively low thermodynamic stability. Here, we simulate the spontaneous insertion and folding of GlpG into a bilayer. An energy landscape analysis of the simulations suggests that GlpG folds via sequential insertion of helical hairpins. The rate-limiting step involves simultaneous insertion and folding of the final helical hairpin. The striking features of GlpG’s experimentally measured landscape can therefore be explained by a partially inserted metastable state, which leads us to a reinterpretation of the rates measured by force spectroscopy. Our results are consistent with the helical hairpin hypothesis but call into question the two-stage model of membrane protein folding as a general description of folding mechanisms in the presence of bilayers.

Date: 2018
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DOI: 10.1038/s41467-018-07320-9

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