Calcium inhibits penetration of Alzheimer's Aβ1–42 monomers into the membrane

Abstract Calcium ion regulation plays a crucial role in maintaining neuronal functions such as neurotransmitter release and synaptic plasticity. Copper (Cu2+) coordination to amyloid‐β (Aβ) has accelerated Aβ1–42 aggregation that can trigger calcium dysregulation by enhancing the influx of calcium ions by extensive perturbing integrity of the membranes. Aβ1–42 aggregation, calcium dysregulation, and membrane damage are Alzheimer disease (AD) implications. To gain a detail of calcium ions' role in the full‐length Aβ1–42 and Aβ1‐42‐Cu2+ monomers contact, the cellular membrane before their aggregation to elucidate the neurotoxicity mechanism, we carried out 2.5 μs extensive molecular dynamics simulation (MD) to rigorous explorations of the intriguing feature of the Aβ1–42 and Aβ1–42‐Cu2+ interaction with the dimyristoylphosphatidylcholine (DMPC) bilayer in the presence of calcium ions. The outcome of the results compared to the same simulations without calcium ions. We surprisingly noted robust binding energies between the Aβ1–42 and membrane observed in simulations containing without calcium ions and is two and a half fold lesser in the simulation with calcium ions. Therefore, in the case of the absence of calcium ions, N‐terminal residues of Aβ1–42 deeply penetrate from the surface to the center of the bilayer; in contrast to calcium ions presence, the N‐ and C‐terminal residues are involved only in surface contacts through binding phosphate moieties. On the other hand, Aβ1–42‐Cu2+ actively participated in surface bilayer contacts in the absence of calcium ions. These contacts are prevented by forming a calcium bridge between Aβ1–42‐Cu2+ and the DMPC bilayer in the case of calcium ions presence. In a nutshell, Calcium ions do not allow Aβ1–42 penetration into the membranes nor contact of Aβ1–42‐Cu2+ with the membranes. These pieces of information imply that the calcium ions mediate the membrane perturbation via the monomer interactions but do not damage the membrane; they agree with the western blot experimental results of a higher concentration of calcium ions inhibit the membrane pore formation by Aβ peptides.


| INTRODUCTION
Over 50 million people succumbed to Alzheimer disease (AD) worldwide is expected to double every 20 years, reaching 75 million in 2030 and 131.5 million in 2050 unless scientists predict effective therapeutic strategies. 1 AD is the most prevalent cause of dementia, accounting for up to 80% of all dementia diagnoses and is characterized by the formation of amyloid β (Aβ) plaques constituted by the aggregation of Aβ peptides, which are produced from the transmembrane amyloid precursor protein (APP) after being cleaved by βand γ-secretases. 2 In the case of the healthy brain, Aβ peptides are in monomeric forms soluble in nature. In contrast, in the case AD affected brain, the peptides aggregate into soluble oligomers and then insoluble fibrils 3 resulting in the formation of plaques. 4 Aβ 1-42 exerts more hydrophobicity in comparison to Aβ 1-40 , driving aggregationprone structure; thus, Aβ 1-42 is the abundant species in senile plaques. 5 The soluble oligomers contribute to several events in AD pathogenesis, including membrane permeability, mitochondrial damage, oxidation stress, and calcium dysregulation. 6,7 Using in silico, in vitro, and in vivo experiments, we found 7 that Aβ 1-42 peptides triggered neurotoxicity, synaptic toxicity, calcium dyshomeostasis, and memory impairment in AD mice brains. Although a large number of experiments 8 have addressed the interaction of oligomeric and fibrils of Aβ peptides with model membranes and some of the theoretical investigations [9][10][11][12][13][14] have studied the monomers, oligomers, and fibril with close contact with the membranes; so far, the underlying mechanism has not been fully elucidated. Still, the interaction of peptides with the membranes is an essential to unveiling neurotoxicity. The interaction of the Aβ peptide with the membrane bilayer depends upon the peptide concentration. For instance, the monomeric peptides have been found binding to the membrane at lower concentration (≤150 nM), 13 while the higher peptide concentration induced oligomeric peptide interaction with the membrane. 12 In particular, small oligomer rather than larger aggregates exerts elevated binding affinity with the membrane. 15 Elevated concentrations of copper ions (400 μM) have been observed in the postmortem AD brain and associated with several neurodegenerative disordered. 16   have given rise to the hypothesis that Cu 2+ ions bound to Aβ 1-42 peptides are involved in three main intertwined pathological events to neuronal cell death; (a) overproducing reactive oxygen species (ROS) contributing to oxidation stress, (b) inducing Aβ 1-42 peptides aggregation mediates neuronal damage by forming membrane perforation, and (c) an enhancement in intracellular calcium levels. The toxicity induced by Aβ 1-42 -Cu 2+ peptides aggregations is well correlated with peptidemembrane interactions. 20 To characterize the effect of copper ions in the Aβ aggregation process, in our two previous papers 21,22 we elucidated that Cu 2+ binding promotes a higher solvation free energy (more hydrophobic) in Aβ 1-42 peptides. The greater water-mediated attraction propensity dictates the fastest self-assembly of Aβ 1-42 -Cu 2+ compared to Aβ 1-42 .
However, previous simulations of Aβ 1- 42 and Aβ 1-42 -Cu 2+ monomers were modeled aqueous phase; their behavior in the cellular environment is still lacking, which is essential to revealing the toxicity mechanism that has been shown to Aβ oligomers' direct contact with the neuronal membranes.
On the other hand, in 1989,"calcium hypothesis of brain aging proposed 23 that Ca 2+ ions are indispensable element for brain function contributing to neurotransmission release, synaptic plasticity, and gene expression. The uncontrollable in and out Ca 2+ transport of cellular membranes occurred in the AD brain induced by Aβ aggregation in hippocampal neurons. This effect mediated cognitive dysfunctions by generating neuroinflammation, synaptic failure, neurotoxicity, and synaptic plasticity. 24 Thus, the relationship between Aβ and Ca 2+ ions reinforce the cognitive deficits in AD patients.
Mounting evidence 19,[25][26][27][28][29] envisaged the membrane attracted Aβ peptides through electrostatic interaction. Subsequently, the peptides penetrating the membrane were driven by hydrophobic interaction of the peptides' central hydrophobic and C-terminal residues with the membranes. Many studies 19,[30][31][32] have been intensively investigated the consequence of free and copper-bound Aβ peptide's interaction with the membrane. Notably, experimental [33][34][35] and computational [36][37][38][39] evidence accounted that calcium ions strongly interact with zwitterionic phosphatidylcholine lipid bilayers. One possible mechanism expects that calcium ions influence these peptides' binding to the zwitterionic lipid bilayer closely related to neuronal toxicity. Exploring the interaction of free and copper-bound full-length Aβ 1-42 monomeric peptides with the membrane in the presence of Ca 2+ concentration is an initial step to identifying the aggregation and cytotoxicity that is still elusive. However, capturing these transition interactions at the atomistic level is challenging with the experimental method. Thus, to best of our knowledge, we first address this problem in the present work by employing rigorous explicit water microsecond molecular dynamics (MD) simulations.
MD simulations of Aβ 1-42 and Aβ 1-42 -Cu 2+ monomers interacting with zwitterionic DMPC bilayer in the presence and absence 40 of calcium ions concentration. In the case of the absence of calcium ions, N-terminal residues of Aβ 1-42 deeply penetrate from the surface to the center of the bilayer, and C-terminal of residues of Aβ 1-42 -Cu 2+ can participate in surface penetration by binding phosphate moieties. 40 In the case of the presence of calcium ions, our present simulation results revealed that N-terminal and C-terminal residues of Aβ 1-42 were involved in surface contacts by binding phosphate moieties; these contacts disappeared in the case of Aβ 1-42 -Cu 2+ . These observations imply that Ca 2+ ions play a significant role in preventing the Aβ 1-42 peptide penetration into the membrane and inhibiting contact of Aβ 1-42 -Cu 2+ with the membrane.

| Simulation set up
We have performed extensive MD simulations to characterize the Aβ 1-42 and Aβ 1-42 -Cu 2+ peptide dynamics on DMPC lipid membranes coincubated with Ca 2+ ions ( Figure 1A,B); simulation details are tabulated in Table 1. Man et al. 44 have demonstrated that the five force fields, AMBER99SB-ILDN, AMBER14SB, CHARMM22*, CHARMM36, and CHARMM36m, are the best candidates among 17 atomic molecular-mechanics force fields for Aβ peptide studies.
Subsequently, Krupa et al. 45 reported results from CHARMM36m and AMBERFF14SB MD simulations on Aβ peptide, which corroborated with experimental data. When the peptides and membranes were in the simulation, AMBERFF14SB and LIPID14 rendered optimal accuracy for the lipids-peptides systems because the primary force field gives a similar result to the latter one. 46 Thus, in the present F I G U R E 1 (A) Initial geometry for simulation containing DMPC bilayer, full-length of Aβ 1-42 (van der Waals representations), and water (blue) and CaCl 2 ions (hidden for clarity purpose) and (B) Cu 2+ bound full-length Aβ 1-42 peptide (van der Waal representation), C, N, O, S, H, and Cu atoms shown in cyan, blue, red, yellow, white and green, respectively; phosphorous atoms shown in purple. (C) Metal coordination residues highlighted, Cu 2+ (green ball) coordinates to N and O of Asp1, Nδ of His6, and Nε of His13. (D) The bilayer constituted by choline (S1), phosphate (S2), glycerol (S3), and fatty acids tails (S4 and S5); area per lipid shown in a blue plane and the angle along one of the lipid acyl chains represented by red. (E) Normalized number density profile for the bilayer and the water, and (F) area per lipid plotted against time and red dotted line indicated experimental 41

| Molecular dynamics simulation protocol
The bonded model of the full-length of Aβ 1-42 -Cu 2+ was taken from our previous MD simulation, 47 where Cu 2+ is coordinated to nitrogen and oxygen atoms of Asp1, N δ of His6, and N ε of His13 ( Figure 1C).
Huy et al. 47 have reported force-field parameters between Cu 2+ and the coordination atoms used in the present work (see supporting information S1). The Aβ 1-42 peptide contains three positively charged residues (Arg5, Lys16, and Lys28), six negatively charged residues (Asp1, Glu3, Asp7, Glu11, Glu22, and Asp23), and net charged is À3.  Figure 1D) in which each bilayer leaflet has 77 DMPC lipids arranged in square shape. Notably, the extracellular Ca 2+ concentrations in the brain are 1-2 mM, which accounts for the presence of four calcium ion in our present simulation box size 679 024 Å 3 . Therefore, we performed molecular dynamics simulations by adding a much higher calcium concentration in the simulation box.
The center of mass of phosphorous (P) atoms in each leaflet is ±Zp = $17 Å from midplane Z = 0, and the thickness of the bilayer was $34 Å (D = 2Zp) ( Figure 1E). Several chloride ions were added to neutralize the system, and the net charge of the simulation system was zero. Four significant points were motivated to select the DMPC bilayer: (a) this lipid is abundant in the neuronal cell membrane 48  Information S1) to unveil the interaction mechanism between the peptides and DMPC bilayers in the presence of a high concentration of Ca 2+ ions in terms of structural and thermodynamics description.

| Analysis
Production trajectories were analyzed using the cpptraj program of AMBER16 packages, 58 which was used to obtain root-mean-square deviation (RMSD), secondary structure, solvent accessible surface area, hydrogen bonds pattern, and density of mass analyses. We wrote Perl scripts to analyze the contact map and free-energy calculation (see Supporting Information S1).

| Root mean square deviation
The RMSD 59

| Contact map
We mapped the contact between two residues when the distance between the center of masses of any two residues is below 6.5 Å. In the case of membrane and peptide interactions, contact was considered between these entities when the distance between the center of masses of amino acids and one of the lipid groups (S1-S4) was ≤6.5 Å.

| Solvent accessible surface area
The LCPO method 61

| Hydrogen bonds
Hydrogen bonds were considered when X Y distance in X H…Y is small than 3.5 Å and X H…Y angle is larger than 135 .
where i and j are running over different sets of atoms pairs, each pair contains a different portion of the system, we inspected the intramolecular salt bridge between charged amino acids by selecting twoatom sets, one atom from the positively charged group of N ε (Lys) and N η (Arg), and another atom from the negative group of C γ (Asp) and C δ (Glu). d 0 is the distance between atoms i and j. The value of d 0 was 4.5 Å.

| Area per lipid and NMR order parameter
The area per lipid (A L ) or in-plane area occupied by a given lipid (see blue color in Figure 1D) was measured using the following equation: where L x and L y are the lateral dimensions of the simulation box along the x and y axes, respectively; and n ¼ NL 2 is the number of lipids per leaflet.
Deuterium NMR order parameter (S CD ) describes the lipid arrangement within the membrane. One C H bond vector is shown in the lipid tail. we measure the orientation of vector (red in Figure 1D) with respect to z-axis (bilayer normal) for determine S CD by using the following equation .
where θ is angle between the C H bond vector and the bilayer normal; the angular brackets represent the ensemble average.

| Density of mass analysis
The density of mass for peptides, membranes, and ions was calculated using the density tool in the cpptraj program. Lipid bilayer thickness is determined by measuring the distance between the density of the phosphorous atoms in the upper and lower leaflets.

| Binding free energy
The molecular mechanics-generalized Boltzmann surface area (MM-GBSA) 62 python script along with AMBER16 was used to compute the binding free energy between the peptide and membrane. The snapshots were collected at 100 ps intervals over the 500 ns MD trajectories, and the MM-GBSA calculations were carried out using the following equation: Total binding free energy (ΔG bind ) is the sum of the gas-phase

| Free energy landscape
Free energy surface (FES) 64 of the systems using two reaction coordinates, V = (Rg, RMSD), was computed with Equation (5).
where P(V) is the probability distribution obtained from the MD simulation results and P max is the maximum of the distribution.

| DMPC bilayer is in liquid-ordered phase
Before discuss the Aβ-membrane interaction, we determined the DMPC bilayer's characteristics that behave as a liquid order phase.
We performed 500 ns MD simulation of the DMPC bilayer in the aqueous phase. The mass density profile of lipid bilayer and water along the membrane z-axis is depicted in Figure 1E. In addition, we monitor acyl chain arrangement within the membrane by measuring the order parameter S CH of the C H bonds of all the lipid tails ( Figure 1G). These order parameter values are close to the deuterium NMR experimental data. 43 Notably, these lipid properties values confirmed that the DMPC bilayer is the liquid-ordered phase, which agrees with previous experimental observations. 46,65 The averaged time-dependent of the Cα rmsd, the radius of gyration (Rg), and total solvent-accessible surface area (SASA) indicate that all the simulation systems became stable after 200 ns (Figures 2 and   S1). Since the peptide-membrane complex fluctuated around the equilibrium value after the τ eq ≈ 200 ns, data analysis was carried out in the 200-500 ns range.
Importantly, in comparison to Aβ 1-42 , R4 has provided significant con-     We consider contact between two species when the distance between their COM falls less than 8 Å. In the case of Aβ 1-42 /DMPC, trajectory2 has contact with the membranes between 200 and 500 ns ( Figure 4). Furthermore, we inspected region-wise trajectory2 of peptide relation with the membranes and observed R3 and R4 are most frequently participating in the interaction. In contrast, Figure S1d shows that trajectory2 of Aβ 1-42 -Cu 2+ contacted the membrane in the first 150 ns. After that, it was away from the membranes. This is interpreted as that Aβ 1-42 , rather than Aβ 1-42 -Cu 2+ , forms more frequent contacts with the membranes. (a) long-range contact is considered when there is a separation greater than 24 residues (highlighted by a white square box in Figure 5), (b) medium-range contact, separation is 12-23 residues(red square box), and (c) short-range contacts, separation is between 6 and 11 residues (yellow rectangular). Long-range contact between residues Ser8-Lys16 and Val36-Ala42, medium-range contacts between residues Gly9-His13 and Glu22-Asn27, and short-range contacts between residues Leu17-Ala21 and Gly25-Ala30 were observed in shows the medium-range contacts between residues Phe20-Lys28 and Val36-Ala42 disappeared in the case of Aβ 1-42 -Cu 2+ /DMPC.
The Aβ 1-42 peptide has three positively charged residues (Arg5, Lys16, and Lys28) and six negatively charged residues (Asp1, Glu3, Asp7, Glu11, Glu22, and Asp23); the total charge is À3; hence, 18 salt-bridges are possible between the charged residues. The probability of salt bridges contacts of the Aβ 1-42 /DMPC and Aβ 1-42 -Cu 2+ / DMPC for all trajectories by an average of total frames are shown in Figure 6A,B; the most representative structure of both complexes is displayed in Figure 6C,D. Seven salt-bridges, Arg5-Glu3, Arg5-Glu3, In general, two salt bridges, Glu22-Lys28 and Asp23-Lys28, play an essential role in the β-hairpin structure found in oligomers and fibrils. 67 We determined these two-salt bridge contact populations to be higher in Aβ 1-42 -Cu 2+ /DMPC compared to Aβ 1-42 /DMPC are playing a pivotal role in stabilizing turn conformation at the loop region. In particular, in the case of Aβ 1-42 -Cu 2+ /DMPC, Glu22-Lys28 salt bridge population has two folders higher than another case, and the main feature of this salt bridge is to trigger β-hairpin conformation at Leu17-Glu33 residues by the stabilized turn structure of Glu22-Lys28 connected between two beta-sheet appeared at residue Leu17-Ala21 and Gly29-Gly33 ( Figure 6D). Whereas in the case of Aβ 1-42 /DMPC, unstructured conformation exists in the residues mentioned earlier ( Figure 6D) since the weaker population of Glu22-Lys28 salt-bridge.
Next, we compared these results with our previous investigation of the same peptide without Ca 2+ ions and DMPC bilayer. 22  We carefully inspected the contact variation between Glu22 and Lys28 residues to the distance between C δ of Glu22 and N ε of Lys28   Figure 8 and confirmed Cu 2+ binding could reduce cross-talk between Nterminal and C-terminal.
The FES plot of the Cα RMSD versus the radius of gyration was computed using Equation (3), as shown in Figure 9, and the structural propensities of the most representative conformers are tabulated in  hydrophilicity character, respectively. We found Cu 2+ binding can increase the SASA value of the Aβ 1-42 by 60, 276, and 242 Å 2 in the P1, P2, and P3, respectively ( Table 3).The R1 and R4 have significant contributions to enhancing the hydrophobicity in the P1-P3 states of Aβ 1-42 -Cu 2+ ( Figure S4) through three significant events (a) Cu 2+ binding residues of Asp1, His6, and His13 or His14 in R1 are more exposed to the waters molecules compelling neighboring residues to enhance their hydrophobicity, (b) significant secondary structure changes at helical contents of R4 transforms it into a β-sheet structure that exhibits higher hydrophobicity and (c) increase in the number of hydrogen bonds ranges from 16-17 to 15-21 between amino acids in the full-length of Aβ 1-42 .
Experimental studies 53,54,69,70 have demonstrated that helix contents in the C-terminal of Aβ favor interaction with the lipid bilayer.
This observation is consistent with the present simulation of helical structure formation at C-terminal, which involves interaction with the lipid bilayer by van der Waals in the case of the free peptide. In contrast, Asp1, His6, and His13/His14 involved in Cu 2+ metal coordination at N-terminal facilitate a beta-sheet structure at the C-terminal, leading to decreased mobility and increased hydrophobicity (higher SASA) of the Aβ 1-42 peptide, as a result preventing the interaction with the membranes. Subsequently, another significant change was noted: the salt bridge formation at Glu22-Lys28 promoted a betahairpin conformation at Leu17-Glu33 residues of Aβ 1-42 due to the Cu 2+ coordination (Figure 3).

| Ca 2+ inhibits Aβ monomers' penetration into the membrane
We examined the distribution of amino acids i along the z-axis to the bilayer P (z, i) for each residue in the N-terminal, central-hydrophobic, loop, and C-terminal regions ( Figure S5). In the N-terminal region, the five residues, Arg5, His6, Asp7, Ser8, and Gly9, have a maximum in the range of 13-16 Å, which is less than the average position of the center of masses of phosphorous atoms Zp = $17 Å, indicating that these five residues are inserted into the bilayer. In the Centralhydrophobic and Loop regions, residues Leu17-Ala21 and Glu22-Lys28 have a maximum at distances ca. Z = 22 Å (Z > Zp), indicating that these residues participate in the bilayer surface interactions. In the C-terminal, Val39, Gly38, and Val40 have peaks near Zp, while residues Gly29, Ala30 and Gly37 have a maximum at about 19 Å, meaning that the former residues are inserted in the bilayer and latter residues form strong bilayer surface contacts. These results F I G U R E 8 The 10 topmost clusters for Aβ 1-42 and Aβ 1-42 -Cu 2+ are displayed, and the corresponding population is given in percentage. The helix, beta-sheet, and random coil are highlighted by red, purple, and green, respectively; N-and Cterminal by blue and purple sphere; and Cu 2+ is represented by a silver sphere. Cu 2+ binding residues of Asp1, His6, and His13 are shown in licorice representation.
confirmed that N-and C-terminal residues are involved in the mechanism of bilayer insertion and that the central and those residues at the loop region form contacts with the lipid bilayer.
We also inspected the mechanism of peptide insertion by plotting the density profile for peptide, lipid, and ions versus the z-axis of the lipid bilayer ( Figure 10). The total density of the simulation system, shown in Table 1 Van der Waals (ΔE vdw ), electrostatic (ΔE elec ), and binding free energy (ΔG bind ) between peptide and membrane are tabulated in Table 4. In the case of Aβ 1-42 /DMPC, ΔE vdw value is about À8.0 kcal/ mol lower than the ΔE elec value, implying that van der Waals energy is the dominant contribution to the Aβ 1-42 -DMPC bilayer binding energy (ΔG bind = À5.93 kcal/mol). On the other hand, upon Cu 2+ binding to the Aβ 1-42 peptide both ΔE vdw and ΔE elec values are higher than those found for the unbound Aβ 1-42 . Notably, the total peptidemembrane binding energy (ΔG bind ) is repulsive upon Cu 2+ binding; as T A B L E 3 The structural propensity of the most representative conformers in each minimum energy basin identified from the free energy surface in Figure 9 System Abbreviations: RMSD, root-mean-square deviation; Rg, radius of gyration; SASA, solvent-accessible surface.
F I G U R E 1 0 Density profiles for different atomic groups along with the z-axis coordination of bilayer. The density mass of each group is divided by the number of atoms in each group. R1 contains residues Asp1-Lys16, R2 Leu17-Ala21, R3 Glu22-Lys28, and R4 Gly29-Ala42.
Membrane-peptide complex displayed in the background, where calcium ions showed in silver color, phosphorous atoms in yellow sphere, and peptide in cartoon representation; for clarity, water and Cl À ions are not shown.
a result, Cu 2+ binding can reduce or inhibit the peptide-membrane contact.
We observed that the ΔG bind energy between Aβ We deeply examined the residue contribution to the binding energy in the interaction of the PO 4 group of DMPC bilayer (see Figure 12). We observed two significant changes in Aβ 1-42 /DMPC.

| DISCUSSIONS
It is known that the interaction of Aβ peptides with the neuronal membrane leads to a significant contribution to cognitive deficits associated with AD. Several experimental efforts have been addressed to exploring the interaction between Aβ oligomers and the membranes, 74 for instance, (1) surface plasma resonance spectroscopy 75 has shown that the interaction between Aβ and membrane was weaker for the POPC bilayer compared to the POPG bilayer, On the other hand, the Aβ 1-42 peptides are arranged in parallel orientation with the DPPC bilayers by forming strong electrostatic F I G U R E 1 1 MM-GBSA binding free energies at every averaged 10 ns windows ± standard error over 500 ns simulation for Aβ 1-42 / DMPC and Aβ 1-42 -Cu 2+ /DMPC complexes. The background figure shows the membrane thickness of the latter complexes using the g_lomepro tool, the thickness increases as a red-white-blue color gradient. The result revealed that Aβ 1-42 -Cu 2+ did not perturb the membrane.
T A B L E 4 MMGBSA binding free energy between peptide and membrane (kcal/mol) ± standard deviation for the last 100 ns of trajectory 2 Aβ attraction of anionic N-terminus to the zwitterionic head group. Nevertheless, the same peptide adopted perpendicular arrangement on the anionic DOPS bilayer membrane due to stronger electrostatic repulsion between anionic N-terminus and the anionic head group, drives enhancing peptide-peptide interaction for oligomer formation. 72 In addition, on the DPPC bilayer, the Asp23-Lys28 salt bridge   Figure 2). Interestingly, these observations corroborated with single-molecular microscopy 84,85 experiments study that interactions between Aβ peptides triggered larger aggregates and impeded the Aβ association with the membranes at the hippocampal neurons of the rat.

| CONCLUSION
We have performed microsecond molecular dynamics simulation to explore the intriguing feature of the full-length of Aβ binding reduced the net-charge of monomer to À1, which is attracted to Ca 2+ was significantly decreased, preventing the Aβ 1-42 -Cu 2+ interaction to the membrane.
8. It is worth noting that both Aβ 1-42 and Aβ 1-42 -Cu 2+ monomers undergo a random coil to β-sheet transition in the aqueous phase and helix transition in the membrane phase.
In summary, all the findings demonstrate that electrostatic and van der Waals interactions are the principal driving forces in forming the interaction between the Aβ 1-42 monomer and the membrane. As soon as the peptide-membrane contact is formed, Ca 2+ forms bridges between the monomer and the membrane since the Ca 2+ ions are attracted by the phosphate moieties, resulting in the reduced peptidemembrane binding affinities leading to preventing insertion of the Aβ 1-42 monomer into the DMPC bilayer.
In this work, we presented the relationship between the Aβ monomers and the membranes; we expected that the oligomer form