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

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-...

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Main Authors: Xu, Weixin, Su, Haibin, Mu, Yuguang, Zhang, John Z. H.
Other Authors: School of Materials Science & Engineering
Format: Article
Language:English
Published: 2013
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Online Access:https://hdl.handle.net/10356/97982
http://hdl.handle.net/10220/17172
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spelling sg-ntu-dr.10356-979822020-06-01T10:13:58Z Molecular dynamics simulation study on the molecular structures of the amylin fibril models Xu, Weixin Su, Haibin Mu, Yuguang Zhang, John Z. H. School of Materials Science & Engineering School of Biological Sciences DRNTU::Science::Chemistry::Physical chemistry 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. 2013-10-31T08:32:52Z 2019-12-06T19:49:00Z 2013-10-31T08:32:52Z 2019-12-06T19:49:00Z 2012 2012 Journal Article Xu, W., Su, H., Zhang, J. Z. H., & Mu, Y. (2012). Molecular dynamics simulation study on the molecular structures of the amylin fibril models. The Journal of Physical Chemistry B, 116(48), 13991-13999. https://hdl.handle.net/10356/97982 http://hdl.handle.net/10220/17172 10.1021/jp308708h en The journal of physical chemistry B
institution Nanyang Technological University
building NTU Library
country Singapore
collection DR-NTU
language English
topic DRNTU::Science::Chemistry::Physical chemistry
spellingShingle DRNTU::Science::Chemistry::Physical chemistry
Xu, Weixin
Su, Haibin
Mu, Yuguang
Zhang, John Z. H.
Molecular dynamics simulation study on the molecular structures of the amylin fibril models
description 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.
author2 School of Materials Science & Engineering
author_facet School of Materials Science & Engineering
Xu, Weixin
Su, Haibin
Mu, Yuguang
Zhang, John Z. H.
format Article
author Xu, Weixin
Su, Haibin
Mu, Yuguang
Zhang, John Z. H.
author_sort Xu, Weixin
title Molecular dynamics simulation study on the molecular structures of the amylin fibril models
title_short Molecular dynamics simulation study on the molecular structures of the amylin fibril models
title_full Molecular dynamics simulation study on the molecular structures of the amylin fibril models
title_fullStr Molecular dynamics simulation study on the molecular structures of the amylin fibril models
title_full_unstemmed Molecular dynamics simulation study on the molecular structures of the amylin fibril models
title_sort molecular dynamics simulation study on the molecular structures of the amylin fibril models
publishDate 2013
url https://hdl.handle.net/10356/97982
http://hdl.handle.net/10220/17172
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