The Sequence Dependence of Fiber Organization. A Comparative Molecular Dynamics Study of the Islet Amyloid Polypeptide Segments 22–27 and 22–29

Laboratory of Experimental and Computational Biology, NCI-Frederick, Bldg 469, Rm 151, Frederick, MD 21702, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 07/2003; 329(3):565-84. DOI: 10.1016/S0022-2836(03)00491-1
Source: PubMed


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.

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    • "Furthermore, the significantly prolonged lag time of the control analog 20K-hIAPP(20–29) suggested that the positive charge and/or the bulky side-chain may place a barrier to the assembly of amyloid aggregates. The oligomerization states of IAPP and related fragments have been studied mostly by molecular dynamics simulation and experimental evidence is still necessary [29] [30] [31]. "
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    • "However, from a chemical standpoint they differed solely in their side chains composition, i.e., their sequence. This point appears to be confirmed when revisiting other amyloidogenic sequences and their respective structural models: Aβ 11–25 [37], the Syrian hamster prion protein segment, PrP [28] and the IAPP segments 22–27 and 22–29 [29] [30]: all presented a minimum assembly complex with more than one sheet. Yet, in these peptides, the side chains chemical character respectively varied from highly to moderately hydrophobic. "
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