Modular protein frameworks via supramolecular synthons

Controlled protein assembly and protein crystal engineering are routes to new types of biomaterials. In this review, we examine how crystal engineering concepts, including polymorph searching, molecular tectonics and supramolecular synthons, can be adapted and applied in protein-based systems. We explore 'mix-and-match' approaches, as established with modular frameworks that combine interchangeable components. We review the numerous current methodologies in protein assembly and crystal engineering from (de novo) designed proteins to metal-mediated or ligand-mediated strategies. Commercially available synthetic receptors such as macrocycles are useful protein assembly mediators and are advantageous in their applicability to diverse protein targets. We highlight the use of calixarenes, cucurbiturils and proteins as building blocks (tectons), showing that reproducible inter-tecton structural units (synthons) have applications in directing protein assembly and crystal engineering.