Nucleation and Growth of Amino Acid and Peptide Supramolecular Polymers through Liquid–Liquid Phase Separation

The transition of peptides and proteins from the solution phase into fibrillar structures is a general phenomenon encountered in functional and aberrant biology and is increasingly exploited in soft materials science. However, the fundamental molecular events underpinning the early stages of their assembly and subsequent growth have remained challenging to elucidate. Here, we show that liquid–liquid phase separation into solute‐rich and solute‐poor phases is a fundamental step leading to the nucleation of supramolecular nanofibrils from molecular building blocks, including peptides and even amphiphilic amino acids. The solute‐rich liquid droplets act as nucleation sites, allowing the formation of thermodynamically favorable nanofibrils following Ostwald's step rule. The transition from solution to liquid droplets is entropy driven while the transition from liquid droplets to nanofibrils is mediated by enthalpic interactions and characterized by structural reorganization. These findings shed light on how the nucleation barrier toward the formation of solid phases can be lowered through a kinetic mechanism which proceeds through a metastable liquid phase.     

Stable Prenucleation Calcium Carbonate Clusters Define Liquid–Liquid Phase Separation

Liquid–liquid phase separation (LLPS) is an intermediate step during the precipitation of calcium carbonate, and is assumed to play a key role in biomineralization processes. Here, we have developed a model where ion association thermodynamics in homogeneous phases determine the liquid–liquid miscibility gap of the aqueous calcium carbonate system, verified experimentally using potentiometric titrations, and kinetic studies based on stopped‐flow ATR‐FTIR spectroscopy. The proposed mechanism explains the variable solubilities of solid amorphous calcium carbonates, reconciling previously inconsistent literature values. Accounting for liquid–liquid amorphous polymorphism, the model also provides clues to the mechanism of polymorph selection. It is general and should be tested for systems other than calcium carbonate to provide a new perspective on the physical chemistry of LLPS mechanisms based on stable prenucleation clusters rather than un‐/metastable fluctuations in biomineralization, and beyond.     

Porphyrin/Ionic‐Liquid Co‐assembly Polymorphism Controlled by Liquid–Liquid Phase Separation

Understanding and controlling multicomponent co‐assembly is of primary importance in different fields, such as materials fabrication, pharmaceutical polymorphism, and supramolecular polymerization, but these aspects have been a long‐standing challenge. Herein, we discover that liquid–liquid phase separation (LLPS) into ion‐cluster‐rich and ion‐cluster‐poor liquid phases is the first step prior to co‐assembly nucleation based on a model system of water‐soluble porphyrin and ionic liquids. The LLPS‐formed droplets serve as the nucleation precursors, which determine the resulting structures and properties of co‐assemblies. Co‐assembly polymorphism and tunable supramolecular phase transition behaviors can be achieved by regulating the intermolecular interactions at the LLPS stage. These findings elucidate the key role of LLPS in multicomponent co‐assembly evolution and enable it to be an effective strategy to control co‐assembly polymorphism as well as supramolecular phase transitions.