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Size, orientation and organization of oligomers that nucleate amyloid fibrils: Clues from MD simulations of pre-formed aggregates

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Title Size, orientation and organization of oligomers that nucleate amyloid fibrils: Clues from MD simulations of pre-formed aggregates
 
Creator SRIVASTAVA, A
BALAJI, PV
 
Subject Amyloid
Pre-formed aggregate
Critical nucleus
Aggregation pathway
Unstable oligomer
MOLECULAR-DYNAMICS SIMULATIONS
CROSS-BETA-SPINE
FORMING PEPTIDE
STRUCTURAL STABILITY
SEQUENCE DEPENDENCE
MISFOLDING DISEASES
ALZHEIMERS-DISEASE
TOXICITY
MECHANISM
INSIGHTS
 
Description All-atom MD simulations of pre-formed aggregates of GNNQQNY with variable size (5 to 16 peptides), orientation (parallel or anti-parallel), organization (single or double sheet, with or without twist), charge status of termini and temperature (300 and 330 K) have been performed for 50 ns each (68 simulations: total time = 3.4 mu s). Double-layer systems are stable irrespective of whether the peptides within the sheet are oriented parallel or anti-parallel. The lifetime of single sheet systems is determined by the protonation status, nature of association of peptides and the size of the aggregates. For example, single sheet 8-mers are stable with parallel arrangement and neutral termini, or with anti-parallel arrangement and charged termini. This suggests that the residues flanking the amyloidogenic sequence also play an important role in determining the organization of peptides in an aggregate. Twist of the cross-beta sheets is found to be intrinsic to the aggregates. Main chain H-bonds are key determinants of stability and loss of these H-bonds is followed by disorder and/or dissociation of the peptide despite the presence of side chain hydrogen bonds. Aggregates are inherently asymmetric along the fiber axis and dissociation from the C-edge is observed more often. An aggregate can disintegrate into smaller-sized oligomers or the edge peptides can dissociate sequentially. A variety of dissociation and disintegration events are observed pointing to the existence of multiple pathways for association during nucleation. It appears that a heterogeneous mixture of oligomers of different sizes exist prior to the formation of the critical nucleus. (C) 2012 Elsevier B.V. All rights reserved.
 
Publisher ELSEVIER SCIENCE BV
 
Date 2014-10-14T17:31:52Z
2014-10-14T17:31:52Z
2012
 
Type Article
 
Identifier BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 1824(8)963-973
http://dx.doi.org/10.1016/j.bbapap.2012.05.003
http://dspace.library.iitb.ac.in/jspui/handle/100/14575
 
Language en