Record Details

Interplay of Sequence, Topology and Termini Charge in Determining the Stability of the Aggregates of GNNQQNY Mutants: A Molecular Dynamics Study

DSpace at IIT Bombay

View Archive Info
 
 
Field Value
 
Title Interplay of Sequence, Topology and Termini Charge in Determining the Stability of the Aggregates of GNNQQNY Mutants: A Molecular Dynamics Study
 
Creator SRIVASTAVA, A
BALAJI, PV
 
Subject AMYLOID FIBRIL FORMATION
SIDE-CHAIN INTERACTIONS
PRION PROTEIN SUP35
CROSS-BETA-SPINE
YEAST PRION
STRUCTURAL STABILITY
PEPTIDE GNNQQNY
FORMING PEPTIDE
MISFOLDING DISEASES
SECONDARY STRUCTURE
 
Description This study explores the stabilities of single sheet parallel systems of three sequence variants of (1)GNNQQNY(7), N2D, N2S and N6D, with variations in aggregate size (5-8) and termini charge (charged or neutral). The aggregates were simulated at 300 and 330 K. These mutations decrease amyloid formation in the yeast prion protein Sup35. The present study finds that these mutations cause instability even in the peptide context. The protonation status of termini is found to be a key determinant of stabilities; other determinants are sequence, position of mutation and aggregate size. All systems with charged termini are unstable, whereas both stable and unstable systems are found when the termini are neutral. When termini are charged, the largest stable aggregate for the N2S and N6D systems has 3 to 4 peptides whereas N2D mutation supports oligomers of larger size (5-and 6-mers) as well. Mutation at 2nd position (N2S and N2D) results in fewer H-bonds at the mutated as well as neighboring (Gly1/Gln4) positions. However, no such effect is found if mutation is at 6th position (N6D). The effect of Asn -> Asp mutation depends on the position and termini charge: it is more destabilizing at the 2nd position than at the 6th in case of neutral termini, however, the opposite is true in case of charged termini. Appearance of twist in stable systems and in smaller aggregates formed in unstable systems suggests that twist is integral to amyloid arrangement. Disorder, dissociation or rearrangement of peptides, disintegration or collapse of aggregates and formation of amorphous aggregates observed in these simulations are likely to occur during the early stages of aggregation also. The smaller aggregates formed due to such events have a variety of arrangements of peptides. This suggests polymorphic nature of oligomers and presence of a heterogeneous mixture of oligomers during early stages of aggregation.
 
Publisher PUBLIC LIBRARY SCIENCE
 
Date 2014-12-29T06:29:21Z
2014-12-29T06:29:21Z
2014
 
Type Article
 
Identifier PLOS ONE, 9(5)
1932-6203
http://dx.doi.org/10.1371/journal.pone.0096660
http://dspace.library.iitb.ac.in/jspui/handle/100/17312
 
Language English