title: Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface.
abstract: We used molecular dynamics simulations to explore the effects of asymmetric transbilayer distribution of anionic phosphatidylserine (PS) lipids on the structure of a protein on the membrane surface and subsequent protein-lipid interactions. Our simulation systems consisted of an amyloidogenic, beta-sheet rich dimeric protein (D42) absorbed to the phosphatidylcholine (PC) leaflet, or protein-contact PC leaflet, of two membrane systems: a single-component PC bilayer and double PC/PS bilayers. The latter comprised of a stable but asymmetric transbilayer distribution of PS in the presence of counterions, with a 1-component PC leaflet coupled to a 1-component PS leaflet in each bilayer. The maximally asymmetric PC/PS bilayer had a non-zero transmembrane potential (TMP) difference and higher lipid order packing, whereas the symmetric PC bilayer had a zero TMP difference and lower lipid order packing under physiologically relevant conditions. Analysis of the adsorbed protein structures revealed weaker protein binding, more folding in the N-terminal domain, more aggregation of the N- and C-terminal domains and larger tilt angle of D42 on the PC leaflet surface of the PC/PS bilayer versus the PC bilayer. Also, analysis of protein-induced membrane structural disruption revealed more localized bilayer thinning in the PC/PS versus PC bilayer. Although the electric field profile in the non-protein-contact PS leaflet of the PC/PS bilayer differed significantly from that in the non-protein-contact PC leaflet of the PC bilayer, no significant difference in the electric field profile in the protein-contact PC leaflet of either bilayer was evident. We speculate that lipid packing has a larger effect on the surface adsorbed protein structure than the electric field for a maximally asymmetric PC/PS bilayer. Our results support the mechanism that the higher lipid packing in a lipid leaflet promotes stronger protein-protein but weaker protein-lipid interactions for a dimeric protein on membrane surfaces.
authors.affiliation: Department of Physics, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: sara.y.cheng@utexas.edu.
authors.forename: Sara Y
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA.
authors.forename: George
authors.initials: G
authors.lastname: Chou
authors.affiliation: Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA.
authors.forename: Creighton
authors.initials: C
authors.lastname: Buie
authors.affiliation: Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Vaughn
authors.affiliation: Department of Computer Science, Trinity University, San Antonio, TX 78212, USA.
authors.forename: Campbell
authors.initials: C
authors.lastname: Compton
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: kcheng1@trinity.edu.
authors.forename: Kwan H
authors.initials: KH
authors.lastname: Cheng
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000838:Anions; D019281:Dimerization; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D055672:Static Electricity
chemical_list: D016229:Amyloid beta-Peptides; D000838:Anions; D008051:Lipid Bilayers
keywords: Asymmetric lipid membrane; Beta-amyloid; Molecular dynamics simulations; Protein aggregation; Protein structures on surfaces; Protein–lipid interactions
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