We highlight recent advancements in the reductionist design of peptide-based simple coacervates formed through liquid-liquid phase separation (LLPS) for protocell formation. These simple (homotypic) coacervates are derived from amino acid derivatives, dipeptides, and bioinspired polypeptides. Key features include weak non-covalent interactions, structure–function relationships, molecular encapsulation, and catalytic capabilities, which are essential for developing single-component protocell models.

Abstract

Homotypic coacervates, formed of a single component, are notable for compartmentalization and could serve as artificial cells for our understanding of living cells. Recently, small designer biomolecules have been investigated for liquid–liquid phase separation (LLPS), like intrinsically disordered proteins (IDPs), allowing them to make coacervate droplets spontaneously through associative molecular interactions. In this context, we highlight the recent developments in the reductionist approach for designer biomolecules, particularly amino acid derivatives, dipeptides, and bioinspired polypeptides, which undergo coacervation to create biomimetic protocells. Weak non-covalent molecular interactions usually drive the self-coacervation of biomolecules, and their structure-function properties are crucial for phase separation. Besides this, we discuss the essential parameters required for promising applications of protocell formation to mimic living cells, including the catalytic ability for enzymatic reactions and the sequestration of micro- and macro-molecules. Finally, we provide some perspective and conclude that simple coacervates formed from small peptide building blocks undergo phase separation to form protocells.