Binding of Cytotoxic Aβ25–35 Peptide to the Dimyristoylphosphatidylcholine Lipid Bilayer

Abstract

Aβ25-35 is a short, cytotoxic, and naturally occurring fragment of the Alzheimer's Aβ peptide. To map the molecular mechanism of Aβ25-35 binding to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer, we have performed replica exchange with solute tempering molecular dynamics simulations using all-atom explicit membrane and water models. Consequences of sequence truncation on the binding mechanism have been measured by utilizing as a control our previous simulations probing binding of the longer peptide Aβ10-40 to the same bilayer. The most intriguing feature of Aβ25-35 binding to the DMPC bilayer is a coexistence of two bound states with strikingly different characteristics: a dominant surface-bound state and a less stable inserted state. In the surface-bound state, the peptide samples extended conformations, in which its unbound C-terminal is pointed away from the bilayer. In contrast, in the inserted state, the C-terminal resides deep in the bilayer hydrophobic core. In both states, the N-terminal remains anchored to the bilayer. Free energy landscape analysis reveals that the two states are separated by a moderate barrier, suggesting that Aβ25-35 monomer may frequently interconvert between them. The net effect of Aβ25-35 binding is a minor impact on the bilayer structure, which contrasts with the considerable bilayer perturbations induced by a longer Aβ10-40 peptide penetrating deep into the bilayer core. Therefore, we conclude that the binding mechanisms of Aβ25-35 and Aβ10-40 peptides are different. Potential implications of our results for Aβ25-35 cytotoxicity are discussed. A comparison of experimental data with our findings reveals a good agreement.

Interaction of the β amyloid – Aβ(25–35) – peptide with zwitterionic and negatively charged vesicles with and without cholesterol

“…The change in hyperfine splitting A + (Aβ) - A + (L) of 16-DSE of about 30 mG (Figure 5 – diamonds and triangles) in all four phospholipids unambiguously indicate that there is a population of Aβ(25–35) deep in the bilayer. This result agrees with the findings of Mason et al(Mason et al, 1996) who observed by X-ray diffraction that Aβ(25–53) inserts into the bilayer hydrocarbon core of 1-Palmitoyl-2-oleoyl phosphatidylcholine (POPC) vesicles, as well as with the results of Dante et al(Dante et al, 2002), Dies et al(Dies et al, 2014) Labbe et al(Labbé et al, 2013) and Smith et al(Smith and Klimov, 2018) which are discussed above. The circle and square symbols at the lower temperatures in Figure 5 point to the second population of Aβ(25–35).…”

“…The circle and square symbols at the lower temperatures in Figure 5 point to the second population of Aβ(25–35). The weak effect Aβ(25–35) on the surface of the vesicles can be explained by the MD simulation results of Smith et al(Smith and Klimov, 2018) in which the authors suggest that the surface-bound peptides point away from the vesicle surface. The temperature behavior of A + (Aβ) - A + (L) of TP (blue and red symbols in Figure 5) supports this interpretation, since the peptide conformation very likely becomes more extended with increasing temperature, which causes the decrease in the magnitude of A + (Aβ) - A + (L), as observed in Figure 5.…”

“…The results of Labbe et al indicate that Aβ(25–35) seems to intercalate within the bilayer altering the lipid chain order (Labbé et al, 2013). Replica exchange with solute tempering (REST) molecular dynamics (MD) simulations(Smith and Klimov, 2018) have been used to study the molecular mechanism of Aβ(25–35) to the zwitterionic DMPC bilayer. According to these MD simulations, there are two populations of Aβ(25–35): a dominant surface-bound population and a less stable inserted population.…”

“…One population of Aβ (25–35), regardless of the charge nature of the vesicle surface, unambiguously inserts in the phospholipid bilayer below the headgroups as has been shown in previous studies. (Dante et al, 2002; Dies et al, 2014; Smith and Klimov, 2018; Labbé et al, 2013) Contrary to D’Errico et al, (2008) the changes in A + in the case of negatively charged DOPG and EPG phospholipid vesicles indicate that not only are the hydrophobic interactions important for the insertion Aβ (25–35) into the bilayer, but also the electrostatic interaction between Aβ and the negatively charged phospholipids. This finding agrees with the conclusion of Esposito et al(2006) According to our results, the second population Aβ (25–35) weakly interacts with the surface of vesicles.…”

“…Frozza et al(Frozza et al, 2009) have presented strong evidence that Aβ(25–35) and Aβ(1–42) peptides induce similar neural injury, and thereby they recommended Aβ(25–35) as a convenient alternative for the investigation of neurotoxic mechanisms involved in AD. Also, several characteristics of Aβ(25–35) such as its amphiphilic nature, aggregation, neurotoxicity and ability to form β-sheet-rich fibrils are similar to those of the full-length Aβ peptide, ( Tsai et al, 2014; Smith and Klimov, 2018) and therefore Aβ(25–35) is a biologically active region of the full-length peptide (Smith and Klimov, 2018; Cuco et al, 2016). Ultimately, an understanding of how the Aβ(25–35) peptides change the fluidity and dielectric properties of the membrane may provide new insights on the mechanisms of the neurodegenerative process associated with AD.…”