Zhuang W, Sgourakis NG, Li Z, Garcia AE, Mukamel S.
Discriminating early stage A{beta}42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study.
Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15687-92.
PubMed.
The determination of the three-dimensional molecular structure of the neurotoxic form of the β amyloid peptide (Aβ) would constitute a major breakthrough for AD research. This is because it would, for example, open the door for rational drug discovery to find small-molecule blockers or inhibitors of such aggregates. However, the structural biology of AD is so far almost completely disabled. This is because the Aβ peptide is highly disordered in the monomer state, and because soluble toxic aggregates of Aβ (the enigmatic oligomers) made in the test tube are too large to be studied by solution nuclear magnetic resonance (NMR), too disordered to be crystallized, and, in fact, too unstable to be easily studied by any technique. The situation is different for the amyloid fibrils for which different structures are being determined with good precision using solid-state NMR and electron microscopy. However, most people now believe that the fibrils, which are the end-point of Aβ aggregation, are not involved in the acutely toxic actions of Aβ in the brain.
The denomination ”disordered” for monomeric Aβ means that peptides in solution interconvert among a very large number of conformations. These interconverting conformational states may be simulated, and several laboratories have reported on computational studies of Aβ conformations (e.g., Sgourakis et al., 2007; Yang and Teplow, 2008; Mitternacht et al., 2010). The problem is to distinguish which conformations are relevant to the association of Aβ monomers into toxic aggregates. The interconversion is very rapid—on the nanosecond time scale—and available biophysical and spectroscopic experimental techniques therefore only report on ”average” structures. Hence, computed ensembles of structures may agree with experimental observations even when biologically relevant structures are not present in those ensembles.
Now, Zhuang et al. show how the conformational properties of disordered peptides in general, and Aβ in particular, may be studied using non-linear infrared (IR) spectroscopy. This type of spectroscopy has been around for a couple of decades, but it has, until recently, mostly been used in research in molecular physics and inorganic chemistry. Zhuang et al. suggest using two-dimensional IR (2DIR) at the spectral region of the amide I resonance (1,700 to 1,600 cm-1), and, in particular, a technique called chirality-induced (CI) 2DIR. Simulations of 2DIR and CI 2DIR spectra of hypothetical solutions of Aβ in different conformations convincingly show that different conformations may be distinguished and their interconversion may be observed. And although the actual experiments remain to be carried out, it is good to learn that 2DIR might be a useful addition to the biophysical toolbox that is available for studies of intrinsically disordered peptides such as Aβ and α-synuclein.
Zhuang et al. also discuss the role of a ”hairpin” turn involving residues 34-38 of Aβ. We have also observed this conformational feature in our simulations, and it is not impossible that it is a significant structural feature of Aβ. However, we and others also observe a similar and very strong propensity for a β-hairpin involving residues 17-31 with a turn in the region 23-26 (Yang and Teplow, 2008; Mitternacht et al., 2010). A 23-26 hairpin was also recently shown by us to be present in neurotoxic Aβ oligomers (Sandberg et al., 2010). The hairpin turn at residues 34-38 may, on the other hand, contribute to different structural propensities of Aβ40 and Aβ42, as discussed by some of the present authors in their earlier work (Sgourakis et al., 2007), and hence also to differences in toxicity between oligomers of Aβ40 and Aβ42.
References:
Mitternacht S, Staneva I, Härd T, Irbäck A.
Comparing the folding free-energy landscapes of Abeta42 variants with different aggregation properties.
Proteins. 2010 Sep;78(12):2600-8.
PubMed.
Sandberg A, Luheshi LM, Söllvander S, Pereira de Barros T, Macao B, Knowles TP, Biverstål H, Lendel C, Ekholm-Petterson F, Dubnovitsky A, Lannfelt L, Dobson CM, Härd T.
Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering.
Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15595-600.
PubMed.
Sgourakis NG, Yan Y, McCallum SA, Wang C, Garcia AE.
The Alzheimer's peptides Abeta40 and 42 adopt distinct conformations in water: a combined MD / NMR study.
J Mol Biol. 2007 May 18;368(5):1448-57.
PubMed.
Yang M, Teplow DB.
Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.
J Mol Biol. 2008 Dec 12;384(2):450-64.
PubMed.
Comments
SLU, Uppsala
The determination of the three-dimensional molecular structure of the neurotoxic form of the β amyloid peptide (Aβ) would constitute a major breakthrough for AD research. This is because it would, for example, open the door for rational drug discovery to find small-molecule blockers or inhibitors of such aggregates. However, the structural biology of AD is so far almost completely disabled. This is because the Aβ peptide is highly disordered in the monomer state, and because soluble toxic aggregates of Aβ (the enigmatic oligomers) made in the test tube are too large to be studied by solution nuclear magnetic resonance (NMR), too disordered to be crystallized, and, in fact, too unstable to be easily studied by any technique. The situation is different for the amyloid fibrils for which different structures are being determined with good precision using solid-state NMR and electron microscopy. However, most people now believe that the fibrils, which are the end-point of Aβ aggregation, are not involved in the acutely toxic actions of Aβ in the brain.
The denomination ”disordered” for monomeric Aβ means that peptides in solution interconvert among a very large number of conformations. These interconverting conformational states may be simulated, and several laboratories have reported on computational studies of Aβ conformations (e.g., Sgourakis et al., 2007; Yang and Teplow, 2008; Mitternacht et al., 2010). The problem is to distinguish which conformations are relevant to the association of Aβ monomers into toxic aggregates. The interconversion is very rapid—on the nanosecond time scale—and available biophysical and spectroscopic experimental techniques therefore only report on ”average” structures. Hence, computed ensembles of structures may agree with experimental observations even when biologically relevant structures are not present in those ensembles.
Now, Zhuang et al. show how the conformational properties of disordered peptides in general, and Aβ in particular, may be studied using non-linear infrared (IR) spectroscopy. This type of spectroscopy has been around for a couple of decades, but it has, until recently, mostly been used in research in molecular physics and inorganic chemistry. Zhuang et al. suggest using two-dimensional IR (2DIR) at the spectral region of the amide I resonance (1,700 to 1,600 cm-1), and, in particular, a technique called chirality-induced (CI) 2DIR. Simulations of 2DIR and CI 2DIR spectra of hypothetical solutions of Aβ in different conformations convincingly show that different conformations may be distinguished and their interconversion may be observed. And although the actual experiments remain to be carried out, it is good to learn that 2DIR might be a useful addition to the biophysical toolbox that is available for studies of intrinsically disordered peptides such as Aβ and α-synuclein.
Zhuang et al. also discuss the role of a ”hairpin” turn involving residues 34-38 of Aβ. We have also observed this conformational feature in our simulations, and it is not impossible that it is a significant structural feature of Aβ. However, we and others also observe a similar and very strong propensity for a β-hairpin involving residues 17-31 with a turn in the region 23-26 (Yang and Teplow, 2008; Mitternacht et al., 2010). A 23-26 hairpin was also recently shown by us to be present in neurotoxic Aβ oligomers (Sandberg et al., 2010). The hairpin turn at residues 34-38 may, on the other hand, contribute to different structural propensities of Aβ40 and Aβ42, as discussed by some of the present authors in their earlier work (Sgourakis et al., 2007), and hence also to differences in toxicity between oligomers of Aβ40 and Aβ42.
References:
Mitternacht S, Staneva I, Härd T, Irbäck A. Comparing the folding free-energy landscapes of Abeta42 variants with different aggregation properties. Proteins. 2010 Sep;78(12):2600-8. PubMed.
Sandberg A, Luheshi LM, Söllvander S, Pereira de Barros T, Macao B, Knowles TP, Biverstål H, Lendel C, Ekholm-Petterson F, Dubnovitsky A, Lannfelt L, Dobson CM, Härd T. Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15595-600. PubMed.
Sgourakis NG, Yan Y, McCallum SA, Wang C, Garcia AE. The Alzheimer's peptides Abeta40 and 42 adopt distinct conformations in water: a combined MD / NMR study. J Mol Biol. 2007 May 18;368(5):1448-57. PubMed.
Yang M, Teplow DB. Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences. J Mol Biol. 2008 Dec 12;384(2):450-64. PubMed.
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