Fuel‐Driven Dynamic Combinatorial Peptide Libraries

• Published in: Angewandte Chemie International Edition 2024-10, Vol.63 (42), p.e202407424-n/a
• Main Authors: Späth, Fabian, Soria‐Carrera, Héctor, Stasi, Michele, Sastre, Judit, Kriebisch, Brigitte A. K., Boekhoven, Job
• Format: Article
• Language: English
• Subjects: Amino acids; Chemical reaction cycle; Chemistry; Combinatorial analysis; Combinatorial chemistry; Combinatorial libraries; Complex coacervation; Dynamic combinatorial library; Equilibrium; Exchanging; Fuels; Liquid phases; Liquid-liquid phase separation; Peptide libraries; Peptides; Phase separation; Simple coacervation
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202407424

Dynamic combinatorial chemistry (DCC) creates libraries of molecules that are constantly interchanging in a dynamic combinatorial library. When a library member self‐assembles, it can displace the equilibria, leading to emergent phenomena like its selection or even its replication. However, such dynamic combinatorial libraries typically operate in or close to equilibrium. This work introduces a new dynamic combinatorial chemistry fueled by a catalytic reaction cycle that forms transient, out‐of‐equilibrium peptide‐based macrocycles. The products in this library exist out of equilibrium at the expense of fuel and are thus regulated by kinetics and thermodynamics. By creating a chemically fueled dynamic combinatorial library with the vast structural space of amino acids, we explored the liquid‐liquid phase separation behavior of the library members. The study advances DCCs by showing that peptide structures can be engineered to control the dynamic library′s behavior. The work paves the way for creating novel, tunable material systems that exhibit emergent behavior reminiscent of biological systems. These findings have implications for the development of new materials and for understanding life′s chemistry. This study introduces a new dynamic combinatorial chemistry (DCC) using a catalytic reaction cycle to form transient, out‐of‐equilibrium peptide‐based macrocycles. Fueled by a chemical reaction, the library explores liquid‐liquid phase separation and advances DCC by engineering peptide structures, paving the way for tunable materials exhibiting emergent, life‐like behaviors.