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

David Zanuy, Yair Porat, Ehud Gazit, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)439-455
Number of pages17
JournalStructure
Volume12
Issue number3
DOIs
StatePublished - Mar 2004

Funding

FundersFunder number
Adams Brain Center
National Cancer Institute's Frederick Advanced Biomedical Supercomputing Center
National Institutes of HealthNO1-CO-12400
National Cancer InstituteZ01BC010440
Academy of Leisure Sciences
United States-Israel Binational Science FoundationBSF-2000337
Israel Science Foundation

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