ABSTRACT
There is mounting evidence that Alzheimer's disease progression and severity are linked to neuronal membrane damage caused by aggregates of the amyloid-ß (Aß) peptide. However, the detailed mechanism behind the membrane damage is not well understood yet. Recently, the lipid-chaperone hypothesis has been put forward, based on which the formation of complexes between Aß and free lipids enables an easy insertion of Aß into membranes. In order to test this hypothesis, we performed numerous all-atom molecular dynamics simulations. We studied the complex formation between individual lipids, considering both POPC and DPPC, and Aß and examined whether the resulting complexes would be able to insert into lipid membranes. Complex formation at a one-to-one ratio was readily observed, yet with minimal effects on Aß's characteristics. Most importantly, the peptide remains largely disordered in 1:1 complexes, and the complex does not insert into the membrane; instead, it is adsorbed to the membrane surface. The results change considerably once Aß forms a complex with a POPC cluster composed of three lipid molecules. The hydrophobic interactions between Aß and the lipid tails cause the peptide to fold into either a helical or a ß-sheet structure. These observations provide atomic insight into the disorder-to-order transition that is needed for membrane insertion or amyloid aggregation to proceed.
