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The interaction of α-helical peptides with lipid bilayers is central to our understanding of the physicochemical principles of biological membrane organization and stability. Mutations that alter the position or orientation of an α-helix within a membrane, or that change the probability that the α-helix will insert into the membrane, can alter a range of membrane protein functions. We describe a comparative coarse-grained molecular dynamics simulation methodology, based on self-assembly of a lipid bilayer in the presence of an α-helical peptide, which allows us to model membrane transmembrane helix insertion. We validate this methodology against available experimental data for synthetic model peptides (WALP23 and LS3). Simulation-based estimates of apparent free energies of insertion into a bilayer of cystic fibrosis transmembrane regulator-derived helices correlate well with published data for translocon-mediated insertion. Comparison of values of the apparent free energy of insertion from self-assembly simulations with those from coarse-grained molecular dynamics potentials of mean force for model peptides, and with translocon-mediated insertion of cystic fibrosis transmembrane regulator-derived peptides suggests a nonequilibrium model of helix insertion into bilayers.

Original publication

DOI

10.1016/j.bpj.2011.02.041

Type

Journal article

Journal

Biophys J

Publication Date

20/04/2011

Volume

100

Pages

1940 - 1948

Keywords

Cell Membrane, Cystic Fibrosis Transmembrane Conductance Regulator, Lipid Bilayers, Molecular Dynamics Simulation, Peptides, Protein Binding, Protein Structure, Secondary, Reproducibility of Results, Thermodynamics, Time Factors