Size, orientation and organization of oligomers that nucleate amyloid fibrils: clues from MD simulations of pre-formed aggregates.
Identifieur interne : 000964 ( Ncbi/Curation ); précédent : 000963; suivant : 000965Size, orientation and organization of oligomers that nucleate amyloid fibrils: clues from MD simulations of pre-formed aggregates.
Auteurs : Alka Srivastava [Inde] ; Petety V. BalajiSource :
- Biochimica et biophysica acta [ 0006-3002 ] ; 2012.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Amyloid.
- Amino Acid Sequence, Animals, Humans, Hydrogen Bonding, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Multimerization, Protein Structure, Tertiary.
Abstract
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 330K) have been performed for 50ns each (68 simulations; total time=3.4μs). 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.
DOI: 10.1016/j.bbapap.2012.05.003
PubMed: 22609417
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Balaji</name></author></analytic><series><title level="j">Biochimica et biophysica acta</title><idno type="ISSN">0006-3002</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Amyloid (chemistry)</term><term>Animals</term><term>Humans</term><term>Hydrogen Bonding</term><term>Molecular Dynamics Simulation</term><term>Molecular Sequence Data</term><term>Protein Multimerization</term><term>Protein Structure, Tertiary</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Amyloïde ()</term><term>Animaux</term><term>Données de séquences moléculaires</term><term>Humains</term><term>Liaison hydrogène</term><term>Multimérisation de protéines</term><term>Simulation de dynamique moléculaire</term><term>Structure tertiaire des protéines</term><term>Séquence d'acides aminés</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amyloid</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Humans</term><term>Hydrogen Bonding</term><term>Molecular Dynamics Simulation</term><term>Molecular Sequence Data</term><term>Protein Multimerization</term><term>Protein Structure, Tertiary</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Amyloïde</term><term>Animaux</term><term>Données de séquences moléculaires</term><term>Humains</term><term>Liaison hydrogène</term><term>Multimérisation de protéines</term><term>Simulation de dynamique moléculaire</term><term>Structure tertiaire des protéines</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 330K) have been performed for 50ns each (68 simulations; total time=3.4μs). 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.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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