Chemically Fueled, Active Droplets Prevent the Aging of Peptides into Amyloid-Like Fibers

Protein aggregation
is a hallmark of molecular aging
and is implicated
in various neurodegenerative diseases. Aggregation proceeds via autocatalytic,
thermodynamically favored pathways. Yet in living systems, dynamic,
active regulation and compartmentalizationsuch as in biomolecular
condensatescan suppress or delay such irreversible assembly.
Here, we describe a peptide that exhibits pathway-dependent self-assembly
into either amyloid-like fibers or fuel-driven droplets. The peptide
was designed to undergo chemical activation via a carbodiimide-driven
reaction cycle, which transiently neutralizes its overall charge and
promotes droplet formation. In the absence of fuel, the peptide slowly
self-assembles into stable fibers through an autocatalytic process
resembling amyloid aging. However, upon repeated or continuous fueling,
the peptide forms active droplets that persist for days and remain
resistant to fiber formation. Thus, we demonstrate that the fuel-driven
active state can completely suppress fiber nucleation and growth.
These findings demonstrate that the constant turnover of peptides
through activation and deactivation can act as a kinetic sink, sequestering
peptides and delaying the transition to the thermodynamically favored
fiber state. Our results establish a minimal, chemically controlled
system in which phase behavior and aging can be modulated by energy
input. This work provides new insight into how nonequilibrium processes
can temporally regulate self-assembly, mimicking cellular strategies
for protein homeostasis. More broadly, it offers a model for studying
the prevention of pathological aggregation and opens routes toward
designing synthetic systems that emulate the dynamic regulation of
living matter.