Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.

This study explores the stabilities of single sheet parallel systems of three sequence variants of 1GNNQQNY7, 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...

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Autores principales:	Alka Srivastava, Petety V Balaji
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/808cc9c41f7b46ddb519c4cd17182caf
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spelling	oai:doaj.org-article:808cc9c41f7b46ddb519c4cd17182caf2021-11-18T08:19:53ZInterplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.1932-620310.1371/journal.pone.0096660https://doaj.org/article/808cc9c41f7b46ddb519c4cd17182caf2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24817093/?tool=EBIhttps://doaj.org/toc/1932-6203This study explores the stabilities of single sheet parallel systems of three sequence variants of 1GNNQQNY7, 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.Alka SrivastavaPetety V BalajiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 5, p e96660 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alka Srivastava Petety V Balaji Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.
description	This study explores the stabilities of single sheet parallel systems of three sequence variants of 1GNNQQNY7, 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.
format	article
author	Alka Srivastava Petety V Balaji
author_facet	Alka Srivastava Petety V Balaji
author_sort	Alka Srivastava
title	Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.
title_short	Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.
title_full	Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.
title_fullStr	Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.
title_full_unstemmed	Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.
title_sort	interplay of sequence, topology and termini charge in determining the stability of the aggregates of gnnqqny mutants: a molecular dynamics study.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/808cc9c41f7b46ddb519c4cd17182caf
work_keys_str_mv	AT alkasrivastava interplayofsequencetopologyandterminichargeindeterminingthestabilityoftheaggregatesofgnnqqnymutantsamoleculardynamicsstudy AT petetyvbalaji interplayofsequencetopologyandterminichargeindeterminingthestabilityoftheaggregatesofgnnqqnymutantsamoleculardynamicsstudy
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Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study.

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