. Structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils. PLoS Comput Biol. 2007 Sep;3(9):1727-38. PubMed.


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  1. Hydrophobic Residues Exposed to Solvent: A Cause of Oligomer Toxicity?
    Assembly of proteins into toxic soluble oligomers and highly ordered fibrils is believed to be critical to amyloidogenic diseases associated with protein misfolding and aberrant aggregation. Thus, understanding these processes at atomic resolution has become the center of many computational studies. Computational approaches need to be simplified to enable studies of processes starting from separated protein molecules into ordered aggregates. Cheon et al. employ constant temperature, Monte Carlo simulations and an implicit water protein model which incorporates all atoms but reduces the degrees of freedom to Ramachandran and side-chain torsional angles only. Using a thus simplified computational approach, Cheon et al. study early stages of oligomer and fibril formation of two amyloid-β protein (Aβ) fragments, Aβ(16-22) and Aβ(25-35).

    Cheon et al. demonstrate that the process of aggregation into amorphous versus ordered species is determined by a competition between the hydrophobicity of the primary structure and the tendency of amino acids to form arrays of hydrogen bonds. The two fragments, Aβ(16-22) and Aβ(25-35), differ by the degree of their overall hydrophobicity, with Aβ(16-22) being significantly more hydrophobic than Aβ(25-35). Consequently, Cheon et al. make an important observation that while formation of disordered oligomers, primarily driven by hydrophobic collapse, is significantly stronger in Aβ(16-22), Aβ(25-35) proceeds to form ordered fibril-like aggregates with no significant amount of hydrophobically collapsed oligomers. This conclusion nicely complements a more general work on assembly of polyalanine molecules done in the Hall group [1-4] as well as more particular studies of full-length Aβ assembly done in our group [5-8].

    During the formation of oligomers, hydrophobic residues are buried on the inside, away from the solvent. Later on, when hydrogen bonds start forming, eventually yielding an ordered fibrillar structure, the hydrophobic residues are forced to get more exposed to the solvent. When the fibrillar structure grows from the initial seed, the ratio of surface to volume steadily decreases, decreasing the total solvent exposure of hydrophobic residues. Thus, the intermediate-size oligomers with some β-strand structure are the ones with a maximal solvent exposure of hydrophobic residues. Based on this observation and on the fact that oligomers of intermediate sizes are typically associated with the highest degree of toxic function, Cheon et al. suggest a relationship between the degree of solvent exposure of hydrophobic residues in an assembly and the cytotoxicity of the assembly. This is a very appealing general hypothesis that needs to be tested in future in-vitro and in-vivo studies.


    . Molecular dynamics simulations of spontaneous fibril formation by random-coil peptides. Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16180-5. PubMed.

    . Phase diagrams describing fibrillization by polyalanine peptides. Biophys J. 2004 Dec;87(6):4122-34. PubMed.

    . Kinetics of fibril formation by polyalanine peptides. J Biol Chem. 2005 Mar 11;280(10):9074-82. PubMed.

    . Spontaneous fibril formation by polyalanines; discontinuous molecular dynamics simulations. J Am Chem Soc. 2006 Feb 15;128(6):1890-901. PubMed.

    . Discrete molecular dynamics simulations of peptide aggregation. Phys Rev E Stat Nonlin Soft Matter Phys. 2004 Apr;69(4 Pt 1):041908. PubMed.

    . Molecular dynamics simulation of amyloid beta dimer formation. Biophys J. 2004 Oct;87(4):2310-21. 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.