Shedding Light on the Dock-Lock Mechanism in Amyloid Fibril Growth Using Markov State Models

Marieke Schor, Antonia S. J. S. Mey, Frank Noe, Cait E. MacPhee

Research output: Contribution to journalArticlepeer-review

Abstract

We investigate how the molecular mechanism of monomer addition to a growing amyloid fibril of the transthyretin TTR105-115 peptide is affected by pH. Using Markov state models to extract equilibrium and dynamical information from extensive all atom simulations allowed us to characterize both productive pathways in monomer addition as well as several off pathway trapped states. We found that multiple pathways result in successful addition All productive pathways are driven by the central hydrophobic residues in the peptide. Furthermore, we show that the slowest transitions in the system involve trapped configurations, that is, long-lived metastable states. These traps dominate the rate of fibril growth. Changing the pH essentially reweights the system, leading to clear differences in the relative importance of both productive paths and traps, yet retains the core mechanism.

Original languageEnglish
Pages (from-to)1076-1081
Number of pages6
JournalThe Journal of Physical Chemistry Letters
Volume6
Issue number6
DOIs
Publication statusPublished - 19 Mar 2015

Keywords

  • PEPTIDES
  • DYNAMICS
  • SIMULATIONS
  • PROPAGATION
  • OLIGOMERS
  • PATHWAYS
  • DISEASE
  • AGENTS

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