Stability of Transmembrane Amyloid <i>β</i>-Peptide and Membrane Integrity Tested by Molecular Modeling of Site-Specific A<i>β</i>₄₂ Mutations

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