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

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