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A Simple Lattice Model That Captures Protein Folding, Aggregation and Amyloid Formation

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  • Sanne Abeln
  • Michele Vendruscolo
  • Christopher M Dobson
  • Daan Frenkel

Abstract

The ability of many proteins to convert from their functional soluble state to amyloid fibrils can be attributed to inter-molecular beta strand formation. Such amyloid formation is associated with neurodegenerative disorders like Alzheimer's and Parkinson's. Molecular modelling can play a key role in providing insight into the factors that make proteins prone to fibril formation. However, fully atomistic models are computationally too expensive to capture the length and time scales associated with fibril formation. As the ability to form fibrils is the rule rather than the exception, much insight can be gained from the study of coarse-grained models that capture the key generic features associated with amyloid formation. Here we present a simple lattice model that can capture both protein folding and beta strand formation. Unlike standard lattice models, this model explicitly incorporates the formation of hydrogen bonds and the directionality of side chains. The simplicity of our model makes it computationally feasible to investigate the interplay between folding, amorphous aggregation and fibril formation, and maintains the capability of classic lattice models to simulate protein folding with high specificity. In our model, the folded proteins contain structures that resemble naturally occurring beta-sheets, with alternating polar and hydrophobic amino acids. Moreover, fibrils with intermolecular cross-beta strand conformations can be formed spontaneously out of multiple short hydrophobic peptide sequences. Both the formation of hydrogen bonds in folded structures and in fibrils is strongly dependent on the amino acid sequence, indicating that hydrogen-bonding interactions alone are not strong enough to initiate the formation of beta sheets. This result agrees with experimental observations that beta sheet and amyloid formation is strongly sequence dependent, with hydrophobic sequences being more prone to form such structures. Our model should open the way to a systematic study of the interplay between the factors that lead to amyloid formation.

Suggested Citation

  • Sanne Abeln & Michele Vendruscolo & Christopher M Dobson & Daan Frenkel, 2014. "A Simple Lattice Model That Captures Protein Folding, Aggregation and Amyloid Formation," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-8, January.
  • Handle: RePEc:plo:pone00:0085185
    DOI: 10.1371/journal.pone.0085185
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    References listed on IDEAS

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    1. Christopher M. Dobson, 2003. "Protein folding and misfolding," Nature, Nature, vol. 426(6968), pages 884-890, December.
    2. Rebecca Nelson & Michael R. Sawaya & Melinda Balbirnie & Anders Ø. Madsen & Christian Riekel & Robert Grothe & David Eisenberg, 2005. "Structure of the cross-β spine of amyloid-like fibrils," Nature, Nature, vol. 435(7043), pages 773-778, June.
    3. Da-Wei Li & Sandipan Mohanty & Anders Irbäck & Shuanghong Huo, 2008. "Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment," PLOS Computational Biology, Public Library of Science, vol. 4(12), pages 1-12, December.
    4. Mookyung Cheon & Iksoo Chang & Sandipan Mohanty & Leila M Luheshi & Christopher M Dobson & Michele Vendruscolo & Giorgio Favrin, 2007. "Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils," PLOS Computational Biology, Public Library of Science, vol. 3(9), pages 1-12, September.
    5. Stefan Auer & Filip Meersman & Christopher M Dobson & Michele Vendruscolo, 2008. "A Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric Aggregates," PLOS Computational Biology, Public Library of Science, vol. 4(11), pages 1-7, November.
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