dorsal/arxiv
View SchemaFolding is Not Required for Bilayer Insertion: Replica Exchange Simulations of an a-Helical Peptide with an Explicit Lipid Bilayer
| Authors | Hugh Nymeyer, Thomas B. Woolf, Angel E. Garcia |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0411001 |
| URL | https://arxiv.org/abs/q-bio/0411001 |
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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"abstract": "We implement the replica exchange molecular dynamics algorithm to study the\ninteractions of a model peptide (WALP-16) with an explicitly represented DPPC\nmembrane bilayer. We observe the spontaneous, unbiased insertion of WALP-16\ninto the DPPC bilayer and its folding into an a-helix with a trans-bilayer\norientation. We observe that the insertion of the peptide into the DPPC bilayer\nprecedes secondary structure formation. Although the peptide has some\npropensity to form a partially helical structure in the interfacial region of\nthe DPPC/water system, this state is not a productive intermediate but rather\nan off-pathway trap for WALP-16 insertion. Equilibrium simulations show that\nthe observed insertion/folding pathway mirrors the potential of mean force\n(PMF). Calculation of the enthalpic and entropic contributions to this PMF show\nthat the surface bound conformation of WALP-16 is significantly lower in energy\nthan other conformations, and that the insertion of WALP-16 into the bilayer\nwithout regular secondary structure is enthalpically unfavorable by 5-10\nkcal/mol/residue. The observed insertion/folding pathway disagrees with the\ndominant conceptual model, which is that a surface bound helix is an obligatory\nintermediate for the insertion of a-helical peptides into lipid bilayers. In\nour simulations, the observed insertion/folding pathway is favored because of a\nlarge (\u003e 100 kcal/mol) increase in system entropy that occurs when the\nunstructured WALP-16 peptide enters the lipid bilayer interior. The\ninsertion/folding pathway that is lowest in free energy depends sensitively on\nthe near cancellation of large enthalpic and entropic terms. This suggests that\nintrinsic membrane peptides may have a diversity of insertion/folding behaviors\ndepending on the exact system of peptide and lipid under consideration.",
"arxiv_id": "q-bio/0411001",
"authors": [
"Hugh Nymeyer",
"Thomas B. Woolf",
"Angel E. Garcia"
],
"categories": [
"q-bio.BM"
],
"title": "Folding is Not Required for Bilayer Insertion: Replica Exchange Simulations of an a-Helical Peptide with an Explicit Lipid Bilayer",
"url": "https://arxiv.org/abs/q-bio/0411001"
},
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