• Open Access

STITCHER: Dynamic assembly of likely amyloid and prion β-structures from secondary structure predictions

Authors

  • Allen W. Bryan Jr.,

    1. Harvard/MIT Division of Health Science and Technology, Bioinformatics and Integrative Genomics, E25-519 Cambridge, Massachusetts 02139
    2. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142
    3. MIT Computer Science and Artificial Intelligence Laboratory, The Stata Center, Cambridge, Massachusetts 02139
    Search for more papers by this author
  • Charles W. O'Donnell,

    1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142
    2. MIT Computer Science and Artificial Intelligence Laboratory, The Stata Center, Cambridge, Massachusetts 02139
    Search for more papers by this author
  • Matthew Menke,

    1. MIT Computer Science and Artificial Intelligence Laboratory, The Stata Center, Cambridge, Massachusetts 02139
    Search for more papers by this author
  • Lenore J. Cowen,

    1. Department of Computer Science, Tufts University, Medford, Massachusetts 02155
    Search for more papers by this author
  • Susan Lindquist,

    1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142
    2. Investigator, Department of Biology, MIT, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge MA 02139
    Search for more papers by this author
  • Bonnie Berger

    Corresponding author
    1. MIT Computer Science and Artificial Intelligence Laboratory, The Stata Center, Cambridge, Massachusetts 02139
    2. Department of Mathematics, Massachusetts Institute of Technology, 2-373, Cambridge, Massachusetts 02139
    • 77 Massachusetts Ave., Cambridge, MA 02139
    Search for more papers by this author

Abstract

The supersecondary structure of amyloids and prions, proteins of intense clinical and biological interest, are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Previous work has demonstrated that probability-based prediction of discrete β-strand pairs can offer insight into these structures. Here, we devise a system of energetic rules that can be used to dynamically assemble these discrete β-strand pairs into complete amyloid β-structures. The STITCHER algorithm progressively ‘stitches’ strand-pairs into full β-sheets based on a novel free-energy model, incorporating experimentally observed amino-acid side-chain stacking contributions, entropic estimates, and steric restrictions for amyloidal parallel β-sheet construction. A dynamic program computes the top 50 structures and returns both the highest scoring structure and a consensus structure taken by polling this list for common discrete elements. Putative structural heterogeneity can be inferred from sequence regions that compose poorly. Predictions show agreement with experimental models of Alzheimer's amyloid beta peptide and the Podospora anserina Het-s prion. Predictions of the HET-s homolog HET-S also reflect experimental observations of poor amyloid formation. We put forward predicted structures for the yeast prion Sup35, suggesting N-terminal structural stability enabled by tyrosine ladders, and C-terminal heterogeneity. Predictions for the Rnq1 prion and alpha-synuclein are also given, identifying a similar mix of homogenous and heterogeneous secondary structure elements. STITCHER provides novel insight into the energetic basis of amyloid structure, provides accurate structure predictions, and can help guide future experimental studies. Proteins 2012. © 2011 Wiley Periodicals, Inc.

Ancillary