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Free energy profiles for insertion of a hydrophobic transmembrane protein α-helix (M2 from CFTR) into a lipid bilayer have been calculated using coarse-grained molecular dynamics simulations and umbrella sampling to yield potentials of mean force along a reaction path corresponding to translation of a helix across a lipid bilayer. The calculated free energy of insertion is smaller when a bilayer with a thinner hydrophobic region is used. The free energies of insertion from the potentials of mean force are compared with those derived from a number of hydrophobicity scales and with those derived from translocon-mediated insertion. This comparison supports recent models of translocon-mediated insertion and in particular suggests that: 1), helices in an about-to-be-inserted state may be located in a hydrophobic region somewhat thinner than the core of a lipid bilayer; and/or 2), helices in a not-to-be-inserted state may experience an environment more akin (e.g., in polarity/hydrophobicity) to the bilayer/water interface than to bulk water.

Original publication

DOI

10.1016/j.bpj.2010.08.002

Type

Journal article

Journal

Biophys J

Publication Date

20/10/2010

Volume

99

Pages

2534 - 2540

Keywords

Amino Acid Sequence, Cell Membrane, Cystic Fibrosis Transmembrane Conductance Regulator, Endoplasmic Reticulum, Hydrophobic and Hydrophilic Interactions, Lipid Bilayers, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Structure, Secondary, Thermodynamics