The effect of protonation state on the stability of Amyloid Oligomers assembled from TTR(105-115)

Massimiliano Porrini, Ulrich Zachariae, Perdita E. Barran, Cait E. MacPhee

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    Abstract

    Amyloid fibrils are self-assembled aggregates of polypeptides that are implicated in the development of several human diseases. A peptide derived from amino acids 105–115 of the human plasma protein transthyretin forms homogeneous and well-defined fibrils and, as a model system, has been the focus of a number of studies investigating the formation and structure of this class of aggregates. Self-assembly of TTR(105–115) occurs at low pH, and this work explores the effect of protonation on the growth and stability of small cross-ß aggregates. Using molecular dynamics simulations of structures up to the decamer in both protonated and deprotonated states, we find that, whereas hexamers are more stable for protonated peptides, higher order oligomers are more stable when the peptides are deprotonated. Our findings imply a change in the acid pK of the protonated C-terminal group during the formation of fibrils, which leads to stabilization of higher-order oligomers through electrostatic interactions.
    Original languageEnglish
    Pages (from-to)1233-1238
    Number of pages6
    JournalJournal of Physical Chemistry Letters
    Volume4
    Issue number8
    DOIs
    Publication statusPublished - 27 Mar 2013

    Fingerprint

    Protonation
    oligomers
    Oligomers
    Amyloid
    Peptides
    peptides
    Plasma (human)
    Polypeptides
    polypeptides
    Coulomb interactions
    Self assembly
    Prealbumin
    amino acids
    Molecular dynamics
    self assembly
    Amino acids
    Stabilization
    stabilization
    electrostatics
    molecular dynamics

    Cite this

    Porrini, Massimiliano ; Zachariae, Ulrich ; Barran, Perdita E. ; MacPhee, Cait E. / The effect of protonation state on the stability of Amyloid Oligomers assembled from TTR(105-115). In: Journal of Physical Chemistry Letters. 2013 ; Vol. 4, No. 8. pp. 1233-1238.
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    abstract = "Amyloid fibrils are self-assembled aggregates of polypeptides that are implicated in the development of several human diseases. A peptide derived from amino acids 105–115 of the human plasma protein transthyretin forms homogeneous and well-defined fibrils and, as a model system, has been the focus of a number of studies investigating the formation and structure of this class of aggregates. Self-assembly of TTR(105–115) occurs at low pH, and this work explores the effect of protonation on the growth and stability of small cross-{\ss} aggregates. Using molecular dynamics simulations of structures up to the decamer in both protonated and deprotonated states, we find that, whereas hexamers are more stable for protonated peptides, higher order oligomers are more stable when the peptides are deprotonated. Our findings imply a change in the acid pK of the protonated C-terminal group during the formation of fibrils, which leads to stabilization of higher-order oligomers through electrostatic interactions.",
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    The effect of protonation state on the stability of Amyloid Oligomers assembled from TTR(105-115). / Porrini, Massimiliano; Zachariae, Ulrich; Barran, Perdita E.; MacPhee, Cait E.

    In: Journal of Physical Chemistry Letters, Vol. 4, No. 8, 27.03.2013, p. 1233-1238.

    Research output: Contribution to journalArticle

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    AU - Porrini, Massimiliano

    AU - Zachariae, Ulrich

    AU - Barran, Perdita E.

    AU - MacPhee, Cait E.

    PY - 2013/3/27

    Y1 - 2013/3/27

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    AB - Amyloid fibrils are self-assembled aggregates of polypeptides that are implicated in the development of several human diseases. A peptide derived from amino acids 105–115 of the human plasma protein transthyretin forms homogeneous and well-defined fibrils and, as a model system, has been the focus of a number of studies investigating the formation and structure of this class of aggregates. Self-assembly of TTR(105–115) occurs at low pH, and this work explores the effect of protonation on the growth and stability of small cross-ß aggregates. Using molecular dynamics simulations of structures up to the decamer in both protonated and deprotonated states, we find that, whereas hexamers are more stable for protonated peptides, higher order oligomers are more stable when the peptides are deprotonated. Our findings imply a change in the acid pK of the protonated C-terminal group during the formation of fibrils, which leads to stabilization of higher-order oligomers through electrostatic interactions.

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