title: Lipid insertion domain unfolding regulates protein orientational transition behavior in a lipid bilayer.
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.
authors.affiliation: Department of Physics, Texas Tech University, Lubbock, TX 79409, USA; Department of Physics and Astronomy, Trinity University, San Antonio, TX 78212, USA. Electronic address: biophysics.ttu@gmail.com.
authors.forename: Kwan Hon
authors.initials: KH
authors.lastname: Cheng
authors.affiliation: Department of Physics, Texas Tech University, Lubbock, TX 79409, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Physics, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Sara Y
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA. Electronic address: mark.vaughn@ttu.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Vaughn
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D058767:Protein Unfolding
chemical_list: D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010446:Peptide Fragments; D010713:Phosphatidylcholines; C075222:amyloid beta-protein (1-42); D002784:Cholesterol