title: Folding is not required for bilayer insertion: replica exchange simulations of an alpha-helical peptide with an explicit lipid bilayer.
abstract: We implement the replica exchange molecular dynamics algorithm to study the interactions of a model peptide (WALP-16) with an explicitly represented DPPC membrane bilayer. We observe the spontaneous, unbiased insertion of WALP-16 into the DPPC bilayer and its folding into an alpha-helix with a transbilayer orientation. The free energy surface suggests that the insertion of the peptide into the DPPC bilayer precedes secondary structure formation. Although the peptide has some propensity to form a partially helical structure in the interfacial region of the DPPC/water system, this state is not a productive intermediate but rather an off-pathway trap for WALP-16 insertion. Equilibrium simulations show that the observed insertion/folding pathway mirrors the potential of mean force (PMF). Calculation of the enthalpic and entropic contributions to this PMF show that the surface bound conformation of WALP-16 is significantly lower in energy than other conformations, and that the insertion of WALP-16 into the bilayer without regular secondary structure is enthalpically unfavorable by 5-10 kcal/mol/residue. The observed insertion/folding pathway disagrees with the dominant conceptual model, which is that a surface-bound helix is an obligatory intermediate for the insertion of alpha-helical peptides into lipid bilayers. In our simulations, the observed insertion/folding pathway is favored because of a large (>100 kcal/mol) increase in system entropy that occurs when the unstructured WALP-16 peptide enters the lipid bilayer interior. The insertion/folding pathway that is lowest in free energy depends sensitively on the near cancellation of large enthalpic and entropic terms. This suggests the possibility that intrinsic membrane peptides may have a diversity of insertion/folding behaviors depending on the exact system of peptide and lipid under consideration.
authors.affiliation: Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Nymeyer
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Woolf
authors.forename: Angel E
authors.initials: AE
authors.lastname: Garcia
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D008051:Lipid Bilayers; D010455:Peptides; D015060:1,2-Dipalmitoylphosphatidylcholine