Molecular dynamics simulation study on the molecular structures of the amylin fibril models

Weixin Xu, Haibin Su, John Zhang, Yuguang Mu

Research output: Contribution to journalArticle

Abstract

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 (Biochemistry 2007, 46, 13505-13522) and X-ray (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 β-sheets composed of a limited number of β-strands are stable in the 100-ns simulations, which suggests that steric zipper interactions at a β-sheet-β-sheet interface strongly contribute to the stability of these amyloid aggregates. For both models, outer strands are more flexible, which might coincide 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.

Original languageEnglish (US)
Pages (from-to)13991-13999
Number of pages9
JournalJournal of Physical Chemistry B
Volume116
Issue number48
DOIs
StatePublished - Dec 6 2012

Fingerprint

Islet Amyloid Polypeptide
Molecular structure
Molecular dynamics
molecular structure
molecular dynamics
Computer simulation
simulation
Nuclear magnetic resonance
nuclear magnetic resonance
strands
Amyloid
X rays
x rays
zippers
biochemistry
fibers
Biochemistry
polypeptides
Fibers
Mechanical stability

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Materials Chemistry
  • Surfaces, Coatings and Films

Cite this

Molecular dynamics simulation study on the molecular structures of the amylin fibril models. / Xu, Weixin; Su, Haibin; Zhang, John; Mu, Yuguang.

In: Journal of Physical Chemistry B, Vol. 116, No. 48, 06.12.2012, p. 13991-13999.

Research output: Contribution to journalArticle

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