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

As research progresses toward understanding the role of the amyloid-beta (A beta) peptide in Alzheimer's disease, certain aspects of the aggregation process for A beta 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 A beta aggregation, but the exact nature of the A beta-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 A beta peptide on model zwitterionic dipalmitoylphosphatidylcholine (DPPC) or model anionic dioleoylphosphatidylserine (DOPS) bilayer surfaces. We determined that A beta 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 A beta 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 A beta aggregation.