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Peptide sequence and amyloid formation: Molecular simulations and experimental study of a human islet amyloid polypeptide fragment and its analogs

  1. Author:
    Zanuy, D.
    Porat, Y.
    Gazit, E.
    Nussinov, R.

  2. Author Address

    Nussinov, R, NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, George S Wise Fac Life Sci, Dept Mol Microbiol & Biotechnol, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, Sackler Inst Mol Med, I-69978 Tel Aviv, Israel.
    1. Year: 2004
  2. Journal: Structure
    1. 12
    2. 3
    3. Pages: 439-455
  4. Type of Article: Article
  1. Abstract:

    We present a combined experimental and theoretical investigation of the tendencies to form amyloid fibrils by a hexapeptide derivative of the human islet amyloid polypeptide, the NFGAIL (22-27) fragment and its mutants. We performed a complete alanine scan of this fragment and studied the capability of the wild-type and its mutant analogs to form ordered fibrils by ultrastructural and biophysical analyses. In parallel, we conducted a meticulous characterization of each sequence-complex at an atomistic level by performing nine independent molecular dynamics simulations for a total of 36 ns. These allowed us to rationalize the experimental observations and to establish the role of every residue in the fibrillogenesis. The main factor that determines the formation of regular fibrils is a coherent organization of the intersheet space. In particular, phenylalanine side chains cement the macromolecular assemblies due to their aromatic chemical character and restricted conformational flexibility when interacting with aliphatic residues

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