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Folding is not required for bilayer insertion: Replica exchange simulations of an α‐helical peptide with an explicit lipid bilayer

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 α‐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, 1–3 which is that a surface‐bound helix is an obligatory intermediate for the insertion of α‐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. Proteins 2005. © 2005 Wiley‐Liss, Inc.