Minimalist Molecules Drive Liquid-Liquid Phase Separation to Modularly Assemble Functional Coacervate Protocells

Area of Science:

• Origins of Life Research
• Supramolecular Chemistry
• Synthetic Biology

Background:

• Liquid-liquid phase separation (LLPS) is a key mechanism for protocell formation.
• Identifying minimal molecular components driving LLPS is essential for origin of life studies.
• Ultralow-molecular-weight molecules capable of LLPS are challenging to discover.

Purpose of the Study:

• To design and synthesize minimalist, ultralow-molecular-weight molecules (<300 Da) that undergo LLPS.
• To investigate the fundamental interactions governing LLPS in simple molecular systems.
• To develop versatile molecular building blocks for task-specific coacervates relevant to prebiotic chemistry.

Main Methods:

• Modular synthesis of hydrophobic head-hydrophilic tail molecules (Mw 211-215 Da).
• Analysis of liquid-liquid phase separation (LLPS) driven by these small molecules.
• Characterization of intermolecular interactions and solvation effects on LLPS.
• Construction and testing of functional coacervates for prebiotic reactions.

Main Results:

• Successfully synthesized some of the smallest known phase-separating molecules driving coacervation.
• Demonstrated that LLPS is governed by a balance between non-covalent interactions and solvation.
• Created responsive coacervates (proton, redox, light) and self-fluorescent variants.
• Showcased coacervate ability to accumulate guests and support prebiotic reactions (e.g., C-N coupling, chiral catalysis, DNA hybridization).

Conclusions:

• Established a minimal molecular framework and chemical principles for driving LLPS.
• Advanced the toolkit for origins-of-life research using synthetic coacervates.
• Provided insights into synthetic cell engineering and the minimal requirements for protocell-like behavior.