A molecular dynamics study of the early stages of amyloid-beta(1-42) oligomerization: the role of lipid membranes.

As research progresses toward understanding the role of the amyloid-beta (Abeta) peptide in Alzheimer's disease, certain aspects of the aggregation process for Abeta are still not clear. In particular, the accepted constitution of toxic aggregates in neurons has shifted toward small oligomers. However, the process of forming these oligomers in cells is also not full clear. Even more interestingly, it has been implied that cell membranes, and, in particular, anionic lipids within those membranes, play a key role in the progression of Abeta aggregation, but the exact nature of the Abeta-membrane interaction in this process is unknown. In this work, we use a thermodynamic cycle and umbrella sampling molecular dynamics to investigate dimerization of the 42-residue Abeta peptide on model zwitterionic dipalmitoylphosphatidylcholine (DPPC) or model anionic dioleoylphosphatidylserine (DOPS) bilayer surfaces. We determined that Abeta dimerization was strongly favored through interactions with the DOPS bilayer. Further, our calculations showed that the DOPS bilayer promoted strong protein-protein interactions within the Abeta dimer, whereas DPPC favored strong protein-lipid interactions. By promoting dimer formation and subsequent dimer release into the solvent, the DOPS bilayer acts as a catalyst in Abeta aggregation.