Data showing the lipid conformations and membrane binding behaviors of beta-amyloid fibrils in phase-separated cholesterol-enriched lipid domains with and without glycolipid and oxidized cholesterol from coarse-grained molecular dynamics simulations

The structural conformations of phospholipids and cholesterol in phase-separated lipid domains were determined by surface area, transverse density profile, and lipid acyl chain orientational parameter calculations. Binding kinetics and characterization of membrane-bound states of beta-amyloid fibrils of various sizes (dimer to pentamer), on those lipid domains, were determined using protein residue orientational parameter and fibril-residue-lipid minimum distance analysis methods. The energy of binding and characterization of annular lipid shells surrounding the surface-bound amyloid fibrils were also determined. The calculations described above support the article “Coarse-Grained MD simulations Reveal Diverse Membrane-Bound Conformational States of Beta-Amyloid Fibrils in the Liquid-ordered and Liquid-disordered Regions of Phase-Separated Lipid Rafts Containing Glycolipid, Cholesterol and Oxidized Cholesterol (Cheng et al., 2020 [1])”. The reported data is valuable for the future design and analysis of any protein fibrils binding to phase-separated lipid domains in model multi-component lipids membranes using either atomistic or coarse-grained molecular dynamics simulations. Additionally, this data can guide or validate future single-molecule experiments on fibril/membrane interactions in model or cell membranes.

The reported data is valuable for the future design and analysis of any protein fibrils binding to phase-separated lipid domains in model multi-component lipids membranes using either atomistic or coarse-grained molecular dynamics simulations. Additionally, this data can guide or validate future single-molecule experiments on fibril/membrane interactions in model or cell membranes.
© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license.

Specifications table Subject
Modeling and simulations Specific subject area Analysis of lipid conformations and beta-amyloid fibril binding behaviors in phase-separated lipid raft domains, from molecular dynamics simulated data. Type of data Table  Image  Figure Movie How data were acquired Molecular dynamics simulations of NMR-derived beta-amyloid fibrils and modeled phase-separated lipid raft membranes, using Martini Coarse-Grained Force Fields [2] , molecular dynamics, and GROMACS analysis programs [3] . Data format Raw Parameters for data collection Simulations were performed under physiologically relevant conditions: 300 K, NPT ensemble, 0.1 M sodium chloride salt solution for 20 microseconds for each fibril/raft complex. Description of data collection After positioning fibrils of different sizes, in three different initial locations above the phase-separated lipid rafts of different lipid compositions, molecular dynamics simulations were performed. The final 0-20 microsecond trajectories and energy files were analyzed to create the data. Data

Value of the data
• The data provides useful information about lipid conformations, amyloid-fibril binding behaviours, kinetics, and membrane-bound states, of beta-amyloid fibrils on phase-separated lipid rafts, which mimic the plasma membranes of neurons. • The data will benefit computational and experimental molecular biophysicists interested in amyloid fibril interactions with lipid membranes. Additionally, molecular and cell biologists who are interested in the membrane-disruptive mechanisms of toxic fibrils in model membranes and live cells.
• The fibril's membrane-bound orientations, e.g., surface-bound or inserted, and locations in different lipid domains, e.g., glycolipid or cholesterol-enriched (Lo) or -depleted (Ld), or mixed Lod region, will provide insight to guide future experiments to understand the lipid composition and structures on toxic amyloid binding to cell membranes. The information is also useful for the future design of drug-interventions and new imaging markers, targeting membrane-bound states of amyloid fibrils. • The simulated data will guide the design of proteins that bind to more complex lipid membranes, containing multiple lipid components and varying domain sizes and structures, that provide a more realistic representation of the complex cell membranes. Fig. 1 shows the chemical structures of saturated phospholipid, 1,2-dipalmitoyl-snglycero-3-phosphatidylcholine (DPPC), unsaturated phospholipid, 1,2-dilinoleoyl-sn-glycero-3phosphatidylcholine (DLPC), glycolipid, monosialotetrahexosylganglioside (GM1), cholesterol (CHOL), and three oxidized cholesterols: cholestenone (C1-CHOL), 25-hydroxycholesterol (P1-CHOL) and 4b-hydroxycholesterol (P4-CHOL). The coarse-grained forms of these lipid molecules were used to constructed the multiple component lipid rafts. The chemical structure data files (in sdf format) are given in Supplementary Data (S01). Fig. 2 shows the atomistic structures of beta-amyloid fibrils (PDB: 2BEG) obtained from the experimentally derived pentamer fibril NMR structure [4] . Smaller (dimer, trimer and tetramer) fibril structures were extracted from the original pentamer. All coarse-grained (CG) fibrils (dimer to pentamer) shown in the main article [1] were obtained by using a forward-mapping, or atomistic-to-CG, procedure [5] . The atomistic structure of fibrils can be downloaded from Protein Data Bank (PDB) ( https://www.rcsb.org/structure/2BEG ). The structure file of beta-amyloid fibril pentamer, 2beg.pdb, obtained from PDB is given in Supplementary Data (S02). The surface area of each lipid domain was determined using a grid-based membrane analysis program [6] . All data (in EXCEL) are given in Supplementary Data (S03). Fig. 4 shows the transverse views of lipid phosphate (PO4) headgroup and cholesterol headgroup and tail group in P4-raft and GM-raft, containing DPPC/DLPC/P4-CHOL, and DPPC/DLPC/CHOL/GM1. The number density vs. distance along the z-axis, or number density distributions, of those groups in each lipid domain, Lo, Ld, or Lod, of the two rafts are presented. The image files (in PNG format) and number distribution data (in agr format of xmgrace [7] ) for P4-raft and GM-raft are given in Supplementary Data (S04).  , and 105-130 (chain E) are labeled in blue, red, gray, yellow, and green, respectively. An identical color scheme is used to highlight the fibril backbone (ribbon and loop) and side chains (licorice). The polar residues 6 (E22), 7 (D23), 10 (S26), 11 (N27), and 12 (K28) are shown in thicker licorice. Based on the secondary structure, residues 1-10 (N-terminal), and residues 16-26 (C-terminal) consist of mainly beta-sheets, and the region in between, i.e., residues 11-15 (Loop), is mainly random. A scale bar of 5 Å is shown. Fig. 5 shows the time-averaged lipid orientational order parameters of the ring group of CHOL and acyl chains of DPPC and DLPC in each phase separated lipid domains, Lo, Ld, or Lod, over the last 5 μs of the simulations of CO-raft, C1-raft, P1-raft, P4-raft, and GM-raft, in the absence (no protein) or presence of amyloid fibrils of various sizes (AB, ABC, ABCD, and ABCDE). All data (in EXCEL) are given in Supplementary Data (S05).  Tables 1a-1c show the binding time from fibril-lipid minimum atomic distance kinetics analysis [1] for each lipid, binding location (upper or lower lipid layer) and the equilibrated membrane-bound state of each simulation replicate. The data (in WORD) are given in Supplementary Data (Table S1(a)-(c))

Fibril orientational order in lipid rafts
Figs. 8-12 show the equilibrated membrane-bound states of fibrils at 2 μs for all 60 simulation replicates. The lipids within 0.5 nm from the membrane-bound fibril are shown. The structure files (in PDB) of all 60 replicates are given in Supplementary Data (S08-12).
Figs. 13 and 14 show the fibril orientational order parameter ( −0.5 to 1 with color bar) vs. residue location (horizontal or x-axis and in horizonal color arrows highlighting the fibril chains from N-terminus to C-terminus) and time (vertical or y-axis from 0 to 20 μs) for simulation replicates, CO-ABCD-2 in C-state, CO-ABCD-3 in T-state, C1-ABC-3 in N-state, P1-ABC-2 in I-state, GM-AB-3 in C-state, GM-AB-2 in S-state, GM-ABCD-1 in C-state and GM-ABCD-2 in l -state. The fibril orientational order was calculated from the g_order tool of GROMACS [3] . The color maps are given in Supplementary Data (S13-14).

Minimum-distance analysis of fibril-lipid interactions
Figs. 17-21 show the minimum-distance analysis of all 60 simulation replicates. Each plot shows the minimum distance between atoms of fibril and lipid molecules vs. time (upper panel), number of contacts between lipid and fibril atoms (middle panel) within 2 nm vs. time, and time-averaged minimum distance between atoms of fibril and lipid molecules (lower panel) over the last 5 μs of simulations vs. fibril residue number. Plots of minimum-distance analysis (in agr format of xmgrace [7] ) are given in Supplementary Data (S17-21). Fig. 22 shows the domain resident time% of fibrils in Ld, Lo or Lod domain for all 60 simulation replicates. The Lo resident time is determined as the fraction of time in which the minimum distance between the atoms of fibril and DLPC is greater than 0.5 nm over the entire time of fibril contact with membrane. The Ld resident time is determined as the fraction of time in which the minimum distance between the atoms of fibril and DPPC is greater than 0.5 nm over the entire time of fibril contact with membrane. Finally, the Lod resident time is the time in which Figs. 23-28 show the fibril-lipid minimum distance (0-5 nm with color bar) vs. fibril residue number (horizontal or x -axis and in horizonal color arrows highlighting the fibril chains from Nterminus to C-terminus) and time (vertical or y -axis from 0 to 20 μs) for simulation replicates, in C-state, GM-AB-2 in S-state, GM-ABCD-1 in C-state and GM-ABCD-2 in L -state. All color maps (in PNG) are given in Supplementary Data (S23-28).

Experimental design, materials, and methods
The four ternary lipid rafts (CO-raft, C1-raft, P1-raft and P4-raft) were designed and constructed based on the pre-equilibrated ternary lipid raft reported by Risselada and Marrink [9] . It also represents the control lipid raft (CO-raft). The C1-raft (DPPC/DLPC/C1-CHOL) was constructed by modifying the polarity of the CHOL headgroup from a polar type (SP1) to a non-polar type (C1), i.e., CHOL modified to C1-CHOL. The P1-raft (DPPC/DLPC/P1-CHOL) was constructed by modifying the polarity of the CHOL tail-group from a non-polar type (C1) to a polar type (P1), Each of the five lipid rafts underwent energy minimization and 2 ns pre-equilibration under position-restraint on all lipid and protein atoms to allow proper hydration before the production, removal of position restraints, molecular dynamics simulations for 20 microseconds. The      detailed design, construction and simulation procedures based on Martini Coarse-grained force fields [2] and GROMACS [3] are given in the research article [1] .
Data analysis involves lipid-selection, orientational parameter of lipid and protein, minimumdistance analysis and molecular visualization. The use of data-filtering tool, g_select , from GRO-MACS [3] , to select DPPC-rich Lo-domain, DLPC-rich Ld-domain and mixed Lo/Ld or Lod domain, as well as annular lipid shells, based on the proximity of the lipid and protein atoms upon fibril binding to the lipid membranes. The g_order tool from GROMACS [3] was used to calculate the segmental orientation order of lipid acyl chains and protein fibril chains in each lipid domain or annular lipid shell. The g_mind tool from GROMACS [3] was used to determine the minimumdistance between the atoms of lipid and fibril vs. time, number of atom contacts between lipid and fibril vs. time and the time-averaged minimum-distance between lipid and fibril vs. fibril residue number. The membrane binding time, i.e., the time that the fibril first establishes close contacts to the membrane surface and stays on membrane surface, was determined by the 2D fibril-lipid minimum distance vs. time plots ( Figs. 17 -21 ), and by the 3D minimum-distance vs. fibril residue vs. time plots ( Figs. 24 -28 ). Finally, both the membrane binding time and the stability of the membrane-bound state was determined by the 3D protein orientation vs. residue vs. time plots ( Figs. 13 and 14 ). The molecular visualization of lipid domains and annular lipid shells were also performed using the representation selection tool in Visual Molecular Dynamics program (VMD) [10] .