Entropy-Driven Amino Acid-Based Coacervates with Enzyme-Free Metabolism and Prebiotic Robustness

Protocells capable
of nonenzymatic metabolism and environmental
adaptation are essential models for understanding the emergence of
cellular life. However, existing protocell designs often lack the
robustness or prebiotic relevance to explain how functional supramolecular
assemblies could have formed under early Earth conditions. In this
study, we demonstrate that simple amino acid derivatives, observed
on extraterrestrial bodies and under simulated prebiotic Earth conditions,
undergo entropy-driven liquid–liquid phase separation to form
membraneless protocells through a self-coacervation process. The synergistic
effect of selective enrichment of metabolites and interfacial acceleration
in these coacervate microdroplets enhances enzyme-free reactions,
including sulfur metabolism and prebiotic pigment synthesis. The protocells
are stabilized by water-mediated hydrogen-bonding networks and exhibit
exceptional resilience to prebiotically plausible stressorssuch
as high salinity (up to 4.0 M NaCl), high concentrations of divalent
cations (4.0 M Mg2+/Ca2+), UV radiation, and
extreme temperature fluctuationswhich typically disrupt existing
vesicle-based systems. Remarkably, these structures autonomously generate
and maintain a proton gradient (ΔpH ≈ 0.6–2.1)
across their interfaces, enabling primitive chemiosmotic coupling
via Na+–H+ antiport activity. They also
adaptively remodel into compact spherical morphologies in response
to sudden environmental changes, thereby preserving structural integrity.
By integrating compartmentalization, nonenzymatic catalysis, energy
transduction, and stress tolerance within a minimalist amino acid
framework, our results establish a geochemically plausible pathway
for the formation and persistence of functional protocells. This work
highlights the potential of coacervate-based microcompartments to
bridge nonliving and living systems by sustaining biochemical complexity
under prebiotic conditions.