Stability of Transmembrane Amyloid β-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific Aβ42 Mutations

Abstract

Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer’s disease. Natural mutations in Aβ 42, such as the Arctic mutation (E22G) have been shown to increase Aβ 42 aggregation and neurotoxicity, leading to the early-onset of Alzheimer’s disease. A correlation between the propensity of Aβ 42 to form protofibrils and its effect on neuronal dysfunction and degeneration has been established. Using rational mutagenesis of the Aβ 42 peptide it was further revealed that the aggregation of different Aβ 42 mutants in lipid membranes results in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also have a variable ability to disrupt bilayer integrity. To further test the connection between Aβ 42 mutation and peptide–membrane interactions, we perform molecular dynamics simulations of membrane-inserted Aβ 42 variants (wild-type and E22G, D23G, E22G/D23G, K16M/K28M and K16M/E22G/D23G/K28M mutants) as β-sheet monomers and tetramers. The effects of charged residues on transmembrane Aβ 42 stability and membrane integrity are analyzed at atomistic level. We observe an increased stability for the E22G Aβ 42 peptide and a decreased stability for D23G compared to wild-type Aβ 42, while D23G has the largest membrane-disruptive effect. These results support the experimental observation that the altered toxicity arising from mutations in Aβ is not only a result of the altered aggregation propensity, but also originates from modified Aβ interactions with neuronal membranes.

The Interaction between Amyloid-β Peptides and Anionic Lipid Membranes Containing Cholesterol and Melatonin

“…The peptide takes a slightly tilted orientation, in agreement with computer simulations [85]. The full length A peptide was also found to embed in anionic lipid exclude a membrane-spanning -sheet structure, as it was reported from molecular dynamics simulations [82]–[84].…”

“…From the agreement between calculated and measured electron distribution in Figure 6 b) we do not find evidence for a membrane-spanning -sheet structure, as was reported from molecular dynamics simulations [82]–[84]. This is most likely related to the low peptide concentration of 3 mol%.…”

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

“…This is a result of poor phase space sampling, limited computing resources, and high free energy barriers separating various protein secondary and higher order structures (Buchete and Hummer, 2007; Stefani, 2008; Derreumaux, 2013; Poojari and Strodel, 2013). The use of efficient simulation strategies for effective phase space sampling like multiscale simulations (Derreumaux, 2013; Cheng et al, 2015a; Nasica-Labouze et al, 2015) are needed to further explore protein structures on surfaces, and to uncover deeper insertion states of membrane-active beta-sheet rich proteins.…”

“…This fibril structure has a U-shaped beta-strand-loop-beta-strand motif with an exposed hydrophobic surface in the C-terminal domain that interacts with the cell membranes. Recent molecular dynamics (MD) simulations (Jang et al, 2010; Poojari and Strodel, 2013; Nasica-Labouze et al, 2015) further established the capability of these fibrillar beta-amyloid multimers to form pores in a simple one-component lipid bilayer. At present, the knowledge of early events of protein structural transitions and protein–lipid interactions of any beta-amyloid multimers on asymmetric lipid surfaces that may lead to membrane pore formation is unclear.…”

N‐Terminal Charged Residues of Amyloid‐β Peptide Modulate Amyloidogenesis and Interaction with Lipid Membrane

“…Lys16 is one of the crucial amino acids responsible for anchoring the peptide onto phospholipid membrane. [12, 20] Interestingly, when Lys16 is mutated to a neutral Nle residue, the deposition rate is dramatically decreased compared to the wild type analogue (Aβ40-M5 vs. Aβ40 in Figure 4A), likely due to the increased hydrophobicity of the region caused by mutation (Table S1), thus weakening interactions with the hydrophilic membrane surface. Mutation of Arg5 to an oppositely charged Glu (Aβ40-M8) does not change the deposition rate of the peptide dramatically (Figure 4A), possibly because Arg5 is close to the N-terminal of the sequence and does not contribute much to the electrostatic interactions between the peptide and membrane.…”