Amyloid-β Peptide Interaction with Lipid Bilayer Promotes Peptide Aggregation on the Surface and Modulates Lipid Behavior

Abstract

Alzheimer's disease (AD) is an important, increasingly prevalent neurological disorder. Aggregation of Amyloid-β (Aβ) is important in etiology of AD and the interaction of these peptides with cell membranes is probably one of the key pathological events responsible for neuron cell death in AD. However, the molecular mechanism underlying the interaction is not known. The slow nature of conformational changes of protein and membrane lipids contributes to this void in the literature. To accelerate the membrane contribution to the conformational changes of Aβ without the loss of atomistic detail, we used the novel high mobility mimetic membrane (HMMM) model to investigate the Aβ-membrane interactions using molecular dynamic simulations. These membrane models increase lateral lipid movement by an order of magnitude while maintaining atomistic detail by modeling the lipid tails nearest the membrane center as a fluid organic solvent while maintaining the atomic description of the lipid head-groups. We built three systems: clusters of two and three unfolded Aβ40 peptides inside a membrane bilayer and an Aβ40 dimer with one peptide anchored to the membrane surface. The HMMM lipid composition used was PC:pPE:SM:CHOL 38:27:6:29. The transmembrane Aβ-peptides demonstrated rapid clustering (<50ns) with subsequent β-sheet formation between residues 18-22 of the monomers, concording with experimentally observed Aβ fibril structures and computationally determined dimer structures. The β-sheet formation can potentially lead to creation of a pore inside the membrane that can affect cellular function. The anchored dimer demonstrated increasing inter-peptide β-sheet content and subsequent movement toward the membrane surface, implying a mechanism for nucleation and aggregation of Aβ oligomers. The strong Aβ dimer-membrane interaction lowered the fluidity of the lipid molecules.