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
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.
Available from: Hong Chen
- "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   . "
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ABSTRACT: Of 10 variation sites between sequences of amyloid-resistant porcine islet amyloid polypeptide (pIAPP) and amyloid-prone human IAPP (hIAPP), seven locate within residues 17-29, the most amyloidogenic fragment within hIAPP. To investigate how these variations affect amyloidogenicity, 26 IAPP(17-29) or IAPP(20-29) variants were synthesized and their secondary structures, amyloidogenicity, oligomerization and cytotoxicity were studied. Our results indicated that pIAPP fragments are refractory to amyloid formation and significantly less cytotoxic compared with hIAPP fragments. A novel stable dimer was observed in pIAPP(20-29) solution, whereas hIAPP(20-29) exists mostly as monomers and trimers. Among all human to porcine substitutions, S20R caused the most prolonged lag time and significantly attenuated cytotoxicity. The different oligomerization and amyloidogenic properties of hIAPP and pIAPP fragments are discussed.
FEBS letters 01/2011; 585(1):71-7. DOI:10.1016/j.febslet.2010.11.050 · 3.17 Impact Factor
Available from: David Zanuy
- "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 , the Syrian hamster prion protein segment, PrP  and the IAPP segments 22–27 and 22–29  : 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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ABSTRACT: In this paper we present a detailed atomic model for a protofilament, the most basic organization level, of the amyloid fibre formed by the peptide DFNKF. This pentapeptide is a segment derived from the human calcitonin, a natural amyloidogenic protein. Our model, which represents the outcome of extensive explicit solvent molecular dynamics (MD) simulations of different strand/sheet organizations, is a single beta-sheet filament largely without a hydrophobic core. Nevertheless, this structure is capable of reproducing the main features of the characteristic amyloid fibril organization and provides clues to the molecular basis of its experimental aggregation behaviour. Our results show that the side chains' chemical diversity induces the formation of a complex network of interactions that finally determine the microscopic arrangement of the strands at the protofilament level. This network of interactions, consisting of both side chain-side chain and backbone-side chain interactions, confers on the final single beta-sheet arrangement an unexpected stability, both by enhancing the association of related chemical groups and, at the same time, by shielding the hydrophobic segments from the polar solvent. The chemical physical characterization of this protofilament provides hints to the possible thermodynamical basis of the supra molecular organization that allows the formation of the filaments by lateral association of the preformed protofibrils. Its regular, highly polarized structure shows how other protofilaments can assemble. In terms of structural biology, our results clearly indicate that an amyloid organization implies a degree of complexity far beyond a simple nonspecific association of peptide strands via amide hydrogen bonds.
Physical Biology 07/2004; 1(1-2):89-99. DOI:10.1088/1478-3967/1/2/005 · 2.54 Impact Factor
Available from: Pin Yang
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ABSTRACT: Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear.
Owing to the rapid growth of the oldest age groups of the population and the continuous increase of the incidence of AD, it
has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without
elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular
mechanisms of AD, mainly including Cu2+ and Zn2+ inducing the aggregation of Aβ, catalysing the production of active oxygen species from Aβ, as well as interacting with the
ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is
also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new
dawn that promises the delivery of revolutionary developments for the control of dementias.
Science in China Series B Chemistry 08/2007; 50(4):453-467. DOI:10.1007/s11426-007-0077-x · 1.20 Impact Factor
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