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.

This data article supports the research article entitled “Maximally Asymmetric Transbilayer Distribution of Anionic Lipids Alters the Structure and interaction with Lipids of an Amyloidogenic Protein Dimer Bound to the Membrane Surface” [1]. We describe supporting data on the binding kinetics, time evolution of secondary structure, and residue-contact maps of a surface-absorbed beta-amyloid dimer protein on different membrane surfaces. We further demonstrate the sorting of annular and non-annular regions of the protein/lipid bilayer simulation systems, and the correlation of lipid-number mismatch and surface area per lipid mismatch of asymmetric lipid membranes.

Islet amyloid polypeptide (IAPP) is an intrinsically disordered protein involved in regulating glucose metabolism and gastric emptying. It plays a crucial role in beta cell failure in diabetes type II, where it accumulates in the form of amyloid fibers. Human IAPP (hIAPP) is arguably the most amyloidogenic naturally occurring peptide known so far. Recent work by Raleigh and coworkers shows that a single-point mutation (I26P) converts it into an effective in vitro amyloid inhibitor 1,2. The I26P mutation has been proposed to inhibit fibril formation by affecting the ability of the disordered C terminal tail to rearrange into the amyloid fibril structure, while maintaining intact the conformational properties of the N-terminal region, putatively responsible for the formation of aggregate intermediates 1,2. Though such mechanism has been proposed, the conformational and dynamical properties of the I26P monomer have not been experimentally determined yet. We use tryptophan triplet quenching by cystine to measure the rate of contact formation between the two ends of the I26P peptide. This technique has previously revealed conformational differences between rIAPP and hIAPP 3. It allows detecting both changes in the equilibrium end-to-end distance distribution and in the diffusional dynamics of the end-to-end distance caused by fast reconfigurations of backbone dihedral angles. We compare results for I26P, hIAPP, rIAPP, and model worm like chain peptides of same length. We discuss the effect of proline substitutions on the conformation and dynamics of these intrinsically disordered proteins and their possible effect on amyloid aggregation.