The 3D profile method for identifying fibril-forming segments of proteins

TitleThe 3D profile method for identifying fibril-forming segments of proteins
Publication TypeJournal Article
Year of Publication2006
AuthorsThompson, M. J., Sievers S. A., Karanicolas J., Ivanova M. I., Baker D., & Eisenberg D.
JournalProceedings of the National Academy of Sciences of the United States of America
Date Published2006 Mar 14
KeywordsAmino Acid Sequence, Amyloid, Amyloid beta-Protein, Animals, Biophysical Phenomena, Biophysics, Collaborative Publication, Computer Simulation, Humans, Models, Molecular, Molecular Sequence Data, Muramidase, Myoglobin, Oligopeptides, Peptide Fragments, Protein Structure, Secondary, Proteins, Software, tau Proteins, Thermodynamics

Based on the crystal structure of the cross-beta spine formed by the peptide NNQQNY, we have developed a computational approach for identifying those segments of amyloidogenic proteins that themselves can form amyloid-like fibrils. The approach builds on experiments showing that hexapeptides are sufficient for forming amyloid-like fibrils. Each six-residue peptide of a protein of interest is mapped onto an ensemble of templates, or 3D profile, generated from the crystal structure of the peptide NNQQNY by small displacements of one of the two intermeshed beta-sheets relative to the other. The energy of each mapping of a sequence to the profile is evaluated by using ROSETTADESIGN, and the lowest energy match for a given peptide to the template library is taken as the putative prediction. If the energy of the putative prediction is lower than a threshold value, a prediction of fibril formation is made. This method can reach an accuracy of approximately 80% with a P value of approximately 10(-12) when a conservative energy threshold is used to separate peptides that form fibrils from those that do not. We see enrichment for positive predictions in a set of fibril-forming segments of amyloid proteins, and we illustrate the method with applications to proteins of interest in amyloid research.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
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