We investigate how the
molecular mechanism of monomer addition
to a growing amyloid fibril of the transthyretin <i>TTR</i><sub>105–115</sub> 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