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Folding is Not Required for Bilayer Insertion: Replica Exchange Simulations of an a-Helical Peptide with an Explicit Lipid Bilayer

Hugh Nymeyer·Thomas B. Woolf·Angel E. Garcia
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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 a-helix with a trans-bilayer orientation. We observe 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 a-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 that intrinsic membrane peptides may have a diversity of insertion/folding behaviors depending on the exact system of peptide and lipid under consideration.

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Hugh Nymeyer, Thomas B. Woolf, Angel E. Garcia. 2004-10-29. Folding is Not Required for Bilayer Insertion: Replica Exchange Simulations of an a-Helical Peptide with an Explicit Lipid Bilayer. https://arxiv.org/abs/q-bio/0411001

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