Atomic Mechanisms of Transthyretin Tetramer Dissociation Studied by Molecular Dynamics Simulations

The dissociation of the transthyretin (TTR) tetramer
into a monomer
is closely related to various TTR amyloidoses in humans. While the
tetramer dissociation has been reported to be the rate-limiting step
for TTR aggregation, few details are known about the mechanism. Here,
molecular dynamics (MD) simulations were performed by combining conventional
MD and biased metadynamics to investigate the mechanism for the wild-type
(WT) and mutant (T119M) structures. Both were found to have a great
deal in common. Conventional MD simulations reveal that interfacial
hydrophobic interactions contribute significantly to stabilize the
tetramer. Interfacial residues including L17, V20, L110, and V121
with close contacts form a hydrophobic channel. Metadynamics simulations
indicate that the mouth opening of the hydrophobic channel is the
first and the most difficult step for dissociation. Interactions of
V20 between opposing dimers lock four monomers into the tetramer,
and disruption of the interactions is found to be involved in the
final step. During the dissociation, an increasing extent of solvation
was observed by calculating the radial distribution functions of water
around interfacial hydrophobic residues, suggesting that water plays
a role in driving the tetramer dissociation. Moreover, compared to
T119, residue M119 has a longer side chain that extends into the hydrophobic
channel, making solvation more difficult, consistent with a higher
energy barrier for dissociation of the T119M tetramer. This result
provides a good explanation for the protective role of the T119M mutation.
Overall, this study can provide atomic-level insights to better understand
the pathogenesis of TTR amyloidosis and guide rational drug design
in the future.