The sequence dependence of fiber organization. A comparative molecular dynamics study of the islet amyloid polypeptide segments 22-27 and 22-29

David Zanuy, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Amyloid fiber formation and the possible polymorphism of molecular arrangements depend on the polypeptide length and composition. Here, we seek the chemical clues underlying these processes. Our starting point is based on the experimental observation that some short peptide segments are able to develop fibers that are very similar to those of their original parent proteins. We focus our study on the NFGAILSS peptide, derived from the human islet amyloid polypeptide (residues 22-29). This peptide turned out to be a perfect example, illustrating the fact that the amyloid microscopic organization is highly complex, rather than simply involving hydrogen bond formation. Furthermore, obtaining a reliable molecular model has allowed us to analyze the differences between the amyloid structure we have obtained for this peptide and that obtained for the previously studied, two residues shorter, segment (residues 22-27, NFGAIL). This comparative study yields some clues about chemical events that govern the aggregation of proteins into oriented fibers, such as molecular packing between sheets and the degree of interaction specificity. We characterize the important role played by the hydrophobic and aromatic residues in the inter-sheet association and present new approaches toward the understanding of the nature of events that are likely to take place during fibril formation. These include analysis of interaction patterns derived from specific sheet-associated packing.

Original languageEnglish
Pages (from-to)565-584
Number of pages20
JournalJournal of Molecular Biology
Volume329
Issue number3
DOIs
StatePublished - 6 Jun 2003

Funding

FundersFunder number
Ministry of Science
National Cancer Institute's Frederick Advanced Biomedical Supercomputing Center
National Institutes of HealthNO1-CO-12400
National Cancer InstituteZ01BC010440
Israel Academy of Sciences and Humanities
Israel Science Foundation
Adams Super Center for Brain Studies,Tel Aviv University

    Keywords

    • Amyloid conformation
    • Islet amyloid peptide
    • Molecular dynamics simulation
    • Protein unfolding
    • β-sheet

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