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

Nymeyer, Hugh; Woolf, Thomas B.; Garcia, Angel E.

doi:10.1002/prot.20460

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

Journal Article · Tue Apr 12 00:00:00 EDT 2005 · Proteins

DOI:https://doi.org/10.1002/prot.20460· OSTI ID:819036

Nymeyer, Hugh; Woolf, Thomas B.; Garcia, Angel E.

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.

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE

DOE Contract Number:: W-7405-ENG-36

OSTI ID:: 819036

Report Number(s):: LA-UR-03-2721

Journal Information:: Proteins, Journal Name: Proteins Journal Issue: 4 Vol. 59; ISSN 0887-3585

Publisher:: Wiley

Country of Publication:: United States

Language:: English

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