. Linking folding with aggregation in Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16880-5. PubMed.


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  1. A New Alternative "Endosomic" Amyloid Hypothesis?
    Amyloid β-protein (Aβ), which is believed to play a critical role at early stages of Alzheimer disease (AD), belongs to the group of natively unfolded proteins. Aβ is known to adopt a collapsed coil folded structure in water, whereas in a co-solvent TFE, which is known to stabilize hydrogen bonding, a pH-dependent α-helical folded structure has been found. Another reason why the pH-dependence is important to understand has to do with the fact that different cellular versus extracellular compartments, where Aβ might be present, have different pH values. Specifically, the extracellular environment is typically characterized by a normal pH = 7.4, while early endosomes (compartments inside the cell) have slightly acidic conditions corresponding to pH = 6. Where the earliest events in Aβ assembly take place, inside the cell, outside the cell, or within a cellular membrane, has been an active research topic for many years. Thus, understanding Aβ folding in different solvent conditions and environments is important, because the way the protein folds will directly affect its propensity to assemble as well as impact the structure and function of the assemblies.

    Khandogin and Brooks III studied the pH-dependence of Aβ folded structure of two Aβ fragments: Aβ1-28 containing all ionizable residues of full-length Aβ and Aβ10-42, which is more physiologically relevant to the behavior of full-length Aβ. They applied a relatively novel, continuous constant pH molecular dynamics in which protonation equilibrium is achieved by a microscopic coupling at the atomic level, and which allowed Asp, Glu, His, and α-carboxyl residues to titrate. A replica exchange sampling method, spanning a range of temperatures between 298K and 600K, was used to achieve a rapid convergence to the most energetically favorable conformation. The results showed that the α-helix propensity, which on average never exceeded ~10 percent, was in both Aβ1-28 and Aβ10-42 the highest at pH = 2 and the lowest at pH = 6. Importantly, the specific region in Aβ10-42 that was most susceptible to pH was the central hydrophobic cluster (CHC), L17-A21, while the C-terminal region G29-M35 retained the α-helix propensity of the low pH due to a lack of ionizable residues. Importantly, their calculation of the solvent- exposed surface area (SAS) indicated that the CHC residues were the most exposed to the solvent at pH = 6. These data suggested that this region (CHC) is responsible for the conversion from α-helix to a β-strand in TFE co-solvent upon pH increase from 2 to 6. In contrast, the SAS of the C-terminal region of Aβ10-38 was unaffected by pH due to a lack of ionizable residues.

    Khandogin and Brooks III also assessed β-turn formation in the region A21-A30. This was reported by many independent groups and seems to be present both in a folded Aβ [1] as well as in the Aβ fibrillar structure [2]. The exact location of the β-turn might depend on the Aβ fragment under study, as in the Aβ21-30 decapeptide a turn at V24-K28 [1] and in Aβ10-35 a turn at Glu22-Asn27 [3] were reported. Khandogin and Brooks III found that the β-turn is most probable at pH 4-8 and that the role of the electrostatic interaction Glu22-Lys28 in Aβ1-28 might be particularly important, in agreement with experimental [1] and computational [4,5] studies on Aβ21-30. However, in more physiologically relevant fragments, such as Aβ10-42, Asp23-Lys28 might play a more prominent role, in particular at the level of fibril formation [2]. Khandogin and Brooks III further showed that strong interaction between Glu22 and Lys28 correlated with destabilization of the α-helical structure in the CHC region. Their examination of residue-specific interactions indicated that at pH = 8, hydrophobic residues of CHC are shielded from the solvent due to effective hydrophobic interactions between the CHC and the C-terminal residues Val40, Ile41, and Ala42. This conclusion is consistent with our simulation study using a DMD approach with a four-bead protein model to examine oligomer formation of Aβ1-40 and Aβ1-42 at physiological conditions (pH ~7.4) [6], which determined the presence of strong contacts between the CHC and the C-terminus in Aβ1-42 but not in Aβ1-40 folded monomers and oligomers.

    Interestingly, in our simulations, the strength of electrostatic interactions was minimal, consistent with a lower pH [6]. In fact, including electrostatic interactions involving negatively charged Glu, Asp, and positive charged Lys, Arg, induced formation of larger oligomers in both full-length Aβ peptides [7], consistent with a higher aggregation propensity of Aβ upon increase of pH due to solvent exposure of CHC as observed by Khandogin and Brooks III. Here I want to point out the sequence dependence sensitivity of Aβ structure in both folded and assembly states as observed in our DMD simulations [6,7]. The most surprising result of our simulations of Aβ1-40 and Aβ1-42 folding and oligomer formation was that a difference of two additional amino acids at the C-terminus actually affects the secondary structure and solvent exposure at the N-termini of the two alloforms [6]. Thus, caution is needed when extrapolating data on any Aβ fragment, in particular less physiologically relevant ones, to structure and assembly propensity of full-length peptides.

    In conclusion, Khandogin and Brooks III provide novel and much- needed insights into the pH-dependence of Aβ protein folding and assembly, which was found to be hydrophobically driven and most favorable at pH = 6. As pH = 6 is characteristic of early endosomes, these results, combined with existing experimental studies, suggest a new alternative twist on the amyloid-β hypothesis, stating that the initial steps in Aβ assembly may occur inside the cell before secretion into extracellular space.


    . On the nucleation of amyloid beta-protein monomer folding. Protein Sci. 2005 Jun;14(6):1581-96. PubMed.

    . A structural model for Alzheimer's beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16742-7. PubMed.

    . The Alzheimer's peptide a beta adopts a collapsed coil structure in water. J Struct Biol. 2000 Jun;130(2-3):130-41. PubMed.

    . Folding events in the 21-30 region of amyloid beta-protein (Abeta) studied in silico. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6015-20. PubMed.

    . Solvent and mutation effects on the nucleation of amyloid beta-protein folding. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18258-63. PubMed.

    . In silico study of amyloid beta-protein folding and oligomerization. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17345-50. PubMed.

    . Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Biophys J. 2007 Jun 1;92(11):4064-77. PubMed.

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