  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.
