Christopher Lockhart
Christopher Lockhart
Ph.D. Candidate
George Mason University

17 June 2014 — by Chris Lockhart

A hallmark of Alzheimer's disease is the accumulation of the amyloid β (Aβ) peptide in the brain. As Aβ accumulates, it aggregates into complex structures, forming oligomers (a collection of around 2-12 peptides) or long, insoluble fibrils. Only these aggregated forms are believed to have any cytotoxic effect responsible for Alzheimer's; the presence of a single Aβ peptide in the brain is likely innocuous. The reason for this difference in effect of Aβ depending on its aggregation state is complicated, and thus far this exact question has not been answered by more than 20 years of Alzheimer's research. However, with new computing power and more sophisticated methods, new insights have been made about the amorphous Aβ peptide.

Recent results have shown that aggregation state is largely dependent on the Aβ peptide's secondary structure. In general, a protein can be classified into a few different well-known conformations, including the α-helix, which looks like a cork-screw, the β-sheet, which is a flat and rigid structure, or the random coil, which is effectively the lack of any well-defined structure. The structure of the Aβ fibril is known to be in β-sheet conformation, but the structure of other Aβ aggregates are generally unknown. An interesting work by Nerelius et al. (2009) demonstrated that ligands which are capable of inducing an α-helical conformation in Aβ are effective at stopping aggregation and decreasing Aβ cytotoxicity1. A recent study by our group showed a similar result; by introducing ibuprofen, a known anti-aggregation agent of Aβ, to a single Aβ peptide, we observed a sharp increase in α-helical content 2. It is easy to speculate that the formation of helix in Aβ by ibuprofen is sufficient to stop peptide aggregation and provide ibuprofen's observed therapeutic benefit.

Further probing into Aβ helicity, we started cutting the Aβ peptide into smaller fragments to assess how well its secondary structure is preserved3. The Aβ peptide is most abundantly found in a form which is 40 amino acids in length. In our past work, we have showed that cutting off the first 9 amino acids has negligible effects on Aβ's secondary structure (Fig. 1). It turns out that even cutting off the first 22 amino acids results in a conformation similar to full-length Aβ. If you were continue to cut off amino acids from the peptide, the structure remains the same up until you cut off the first 28 amino acids. After this, the resulting Aβ29-40 fragment adopts a helical structure similar to as seen in our previous simulations featuring ibuprofen (Figs. 2 and 3). This result can be corroborated with experimental evidence which shows that AβX-42 (a slightly longer species of Aβ) fragments are nontoxic when X>=29 4.

Clearly Aβ is a complex molecule, and understanding its structure in different environments is critical to understanding its cytotoxic effect. Toward this end, we have begun simulating Aβ in the presence of cellular membranes5. Our initial results for a single Aβ peptide bound to a membrane showed that Aβ again adopts a helical state and does not significantly disrupt membrane structure. Thus, simulating Aβ aggregrates in water and the presence of cellular membranes must be important to understand what causes Aβ's cytotoxic effect. However, this problem is difficult to answer because it is an order of magnitude larger than current atomic simulations can handle and is on the cutting edge of computational science. We believe that the Compute Against Alzheimer's Disease campaign is integral to achieving the level of computational power necessary to answer these fundamentally important questions.

Figure 1. Structure of Aβ10-40 in water. Green and red balls represent first and last amino acids, respectively. This structure is mostly in random coil and helix content is low.

Figure 2. Structure of Aβ10-40 in the presence of ibuprofen. Green and red balls represent first and last amino acids, respectively. This structure shows the formation of a helix at the end of the peptide near the last amino acid.

Figure 3. Structure of Aβ29-40 in water. Green and red balls represent first and last amino acids, respectively. This structure shows the formation of a helix at the end of the peptide near the last amino acid.


  1. Nerelius, C., Sandegren, A., Sargsyan, H., Raunak, R., Leijonmarck, H., Chatterjee, U., Fisahn, A., Imarisio, S., Lomas, D.A., Crowther, D.C., Strömberg, R., and Johansson, J. α-Helix targeting reduces amyloid-β peptide toxicity. Proc. Natl. Acad. Sci. U. S. A. 2009 , 106, 9191-9196.
  2. Lockhart, C., Kim, S., and Klimov, D.K. Explicit solvent molecular dynamics simulations of Aβ peptide interacting with ibuprofen ligands. J. Phys. Chem. B 2012 , 116, 12922-12932.
  3. Lockhart, C. and Klimov, D.K. Revealing hidden helix propensity in Aβ peptides by molecular dynamics simulations. J. Phys. Chem. B 2013 , 117, 12030-12038.
  4. Fradinger, E.A., Monien, B.H., Urbanc, B., Lomakin, A., Tan, M., Li, H., Spring, S.M., Condron, M.M., Cruz, L., Xie, C.-W., Benedek, G.B., and Bitan, G. C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity. Proc. Natl. Acad. Sci. U. S. A.2008 , 105, 14175-14180.
  5. Lockhart, C. and Klimov, D.K. Alzheimer's Aβ10-40 peptide binds and penetrates DMPC bilayer: an isobaric-isothermal replica exchange molecular dynamics study. J. Phys. Chem. B 2014 , 118, 2638-2648.