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Molecular Dynamics Simulation Study on the Molecular Structures of the Amylin Fibril Models.
MedLine Citation:
PMID:  23145779     Owner:  NLM     Status:  Publisher    
The structural characterization of amyloid fibers is one of the most investigated areas in structural biology. Recently, protofibril models for amylin, i.e., the 37-residue human islet amyloid polypeptide or hIAPP were suggested by two groups based on NMR (Luca et al., Biochemistry 2007;46:13505-13522) and X-ray (Wiltzius et al., Protein Sci 2008;17:1467-1474) techniques. However, there are significant differences in the two models which maybe originate from the polymorphic nature of amylin fibrils. To obtain further insights into the packing and stability features of the different models, we performed a series of molecular dynamics simulations on them. Our analysis showed that even pairs of $\beta$-sheets composed of a limited number of $\beta$-strands are stable in the 100-ns simulations, which suggests that steric zipper interactions at a $\beta$-sheet-$\beta$-sheet interface strongly contribute to the stability of these amyloid aggregates. For both models, outer strands are more flexible, which coincides with the dynamical requirement that outer strands act as growing sites facilitating conformational changes of new incoming chains. Moreover, simulation results showed that the X-ray models are structurally more compact than the NMR models and have more intimate patterns, which lead to more rigid amyloid models. As a result, the X-ray models are energetically more stable than the NMR models. Further modeling analyses verify the most likely amylin fibril model among both NMR and X-ray models. Upon further study of the force-induced dissociation of a single chain from the protofibrils, the binding energy and the mechanical stability of the fibril models are revealed. On these bases, it is possible to reconcile the crystallographic and the NMR data on the basic amylin fiber unit.
Weixin Xu; Haibin Su; John Z H Zhang; Yuguang Mu
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-13
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  -     ISSN:  1520-5207     ISO Abbreviation:  J Phys Chem B     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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