The amyloid-beta (Abeta) peptide is a key aggregate species in Alzheimer's disease. Although important aspects of Abeta peptide aggregation are understood, the initial stage of aggregation from monomer to oligomer is still not clear. One potential mediator of this early aggregation process is interactions of Abeta with anionic cell membranes. We used unconstrained and umbrella sampling molecular dynamics simulations to investigate interactions between the 42-amino acid Abeta peptide and model bilayers of zwitterionic dipalmitoylphosphatidylcholine (DPPC) lipids and anionic dioleoylphosphatidylserine (DOPS) lipids. Using these methods, we determined that Abeta is attracted to the surface of DPPC and DOPS bilayers over the small length scales used in these simulations. We also found supporting evidence that the charge on both the bilayer surface and the peptide affects the free energy of binding of the peptide to the bilayer surface and the distribution of the peptide on the bilayer surface. Our work demonstrates that interactions between the Abeta peptide and lipid bilayer promotes a peptide distribution on the bilayer surface that is prone to peptide-peptide interactions, which can influence the propensity of Abeta to aggregate into higher-order structures.

The amyloid-beta (Abeta) peptide, the 39 to 43 amino acid peptide that plays a substantial role in Alzheimer's disease, has been shown to interact strongly with lipids both in vitro and in vivo. Abeta-lipid interactions have been proposed as a considerable factor in accelerating Abeta aggregation through the templating role of membranes in aggregation disorders. Previous work has shown that anionic lipids are able to significantly increase Abeta aggregation rate and induce a structural conversion in Abeta from a random coil to a beta-structure that is similar to the monomer structure observed in mature fibrils. However, it is unclear if this structural change occurs with the Abeta monomer because of direct interactions with the lipids or if the structural change results from protein-protein interactions during oligomerization. We use extensive replica exchange molecular dynamics simulations of an Abeta monomer bound to a homogeneous model zwitterionic or anionic lipid bilayer. From these simulations, we do not observe any significant beta-structure formation except for a small, unstable beta-hairpin formed on the anionic dioleylphosphatidylserine bilayer. Further, we see that the Asp23-Lys28 salt bridge that plays a role in beta-hairpin formation is not substantially formed on the bilayer surface and that Lys28 preferentially interacts with lipids when bound to the bilayer. These results suggest that the structural conversion seen in experiments are not due to the ordering of monomeric Abeta on the bilayer surface but are a result of protein-protein interactions enhanced by Abeta binding to the cell membrane.

As research progresses towards understanding the role of the amyloid-β (Aβ) in Alzheimer’s disease, certain aspects of the aggregation process for Aβ are still not clear. In particular, the accepted constitution of toxic aggregates in neurons has shifted towards small oligomers. However, the process of forming these oligomers in cells is still not fully 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 Aβ aggregation, but the exact nature of the Aβ-membrane interaction in this process is still unknown. In this work, we use a thermodynamic cycle and umbrella sampling molecular dynamics to investigate dimerization of the 42-residue Aβ peptide on model zwitterionic dipalmitoylphosphatidylcholine (DPPC) or model anionic dioleoylphosphatidylserine (DOPS) bilayer surfaces. We determined that Aβ 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 Aβ dimer, while 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 Aβ aggregation through converting Aβ monomers in solution into Aβ dimers in solution without substantial a free energy cost.

No abstract

Possible model, but simplistic, mechanisms for the action of vitamin K epoxide reductase (VKOR) are investigated with quantum mechanical methods (B3LYP/6-311G**). The geometries of proposed model intermediates in the mechanisms are energy optimized. Finally, the energetics of the proposed (pseudo-enzymatic) pathways are compared. We find that the several pathways are all energetically feasible. These results will be useful for designing quantum mechanical/molecular mechanical method (QM/MM) studies of the enzymatic pathway once three-dimensional structural data are determined and available for VKOR. FIGURE 3. Thiol/disulfide-based mechanism to reduce the vitamin K epoxide to the quinone.FIGURE 4. NADH/NAD ϩ -based mechanism to reduce the vitamin K epoxide to the quinone. DEERFIELD II ET AL.