Lipid insertion domain unfolding regulates protein orientational transition behavior in a lipid bilayer

Biophys Chem. 2015 Nov:206:22-39. doi: 10.1016/j.bpc.2015.06.011. Epub 2015 Jul 4.

Abstract

We have used coarse-grained (CG) and united atom (UA) molecular dynamics simulations to explore the mechanisms of protein orientational transition of a model peptide (Aβ42) in a phosphatidylcholine/cholesterol (PC/CHO) lipid bilayer. We started with an inserted state of Aβ42 containing a folded (I) or unfolded (II) K28-A42 lipid insertion domain (LID), which was stabilized by the K28-snorkeling and A42-anchoring to the PC polar groups in the lipid bilayer. After a UA-to-CG transformation and a 1000ns-CG simulation for enhancing the sampling of protein orientations, we discovered two transitions: I-to-"deep inserted" state with disrupted K28-snorkeling and II-to-"deep surface" state with disrupted A42-anchoring. The new states remained stable after a CG-to-UA transformation and a 200ns-UA simulation relaxation. Significant changes in the cholesterol-binding domain of Aβ42 and protein-induced membrane disruptions were evident after the transitions. We propose that the conformation of the LID regulates protein orientational transitions in the lipid membrane.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Cholesterol / chemistry*
  • Humans
  • Lipid Bilayers / chemistry*
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Peptide Fragments / chemistry*
  • Phosphatidylcholines / chemistry*
  • Protein Structure, Tertiary
  • Protein Unfolding*

Substances

  • Amyloid beta-Peptides
  • Lipid Bilayers
  • Peptide Fragments
  • Phosphatidylcholines
  • amyloid beta-protein (1-42)
  • Cholesterol