Metal-Directed Protein Self-Assembly
Accounts of Chemical Research
CONSPECTUS Proteins are Nature's premier building blocks for constructing sophisticated nanoscale architectures that carry out complex tasks and chemical transformations. It is estimated that 70-80% of all proteins are permanently oligomeric, that is, they are composed of multiple proteins that are held together in precise spatial organization through non-covalent interactions. While it is of great fundamental interest to understand the physicochemical basis of protein self-assembly, the
... of proteinprotein interactions (PPIs) would also allow access to novel biomaterials using Nature's favorite and most versatile building block. With this possibility in mind, we have developed a new approach, Metal Directed Protein Self-Assembly (MDPSA), which utilizes the strength, directionality and selectivity of metal-ligand interactions to control PPIs. At its core, MDPSA is inspired by supramolecular coordination chemistry which exploits metal coordination for the self-assembly of small molecules into discrete, more-or-less predictable higherorder structures. Proteins, however, are not exactly small molecules or simple metal ligands: they feature extensive, heterogeneous surfaces that can interact with each other and with metal ions in unpredictable ways. We will start this Account by first describing the challenges of using entire proteins as molecular building blocks. This will be followed by our work on a model protein (cytochrome cb 562 ) to both highlight and overcome those challenges toward establishing some ground rules for MDPSA. Proteins are also Nature's metal ligands of choice. In MDPSA, once metal ions guide proteins into forming large assemblies, they are by definition embedded within extensive interfaces formed between protein surfaces. These complex surfaces make an inorganic chemist's life somewhat difficult, yet they also provide a wide platform to modulate the metal coordination environment through distant, non-covalent interactions -exactly as natural metalloproteins and enzymes do. We will describe our computational and experimental efforts on restructuring the non-covalent interaction network formed between proteins surrounding the interfacial metal centers. This approach of metal templating followed by the redesign of protein interfaces (Metal-Templated Interface Redesign, MeTIR) not only provides a route to engineer de novo PPIs and novel metal coordination environments, but also carries possible parallels to the evolution of metalloproteins.