Chemists have engineered a protein so that it self-assembles with zinc ions and an organic small molecule to form the first protein-based metal-organic framework (MOF).

Including proteins in MOFs could combine the biocatalytic, electron-transfer, and molecular recognition capabilities of proteins with the separation, storage, and catalysis applications of MOFs.

Traditional MOFs, which have attracted great academic and industrial interest in recent years, consist of organic linkers connecting metal centers. Akif Tezcan at the University of California, San Diego, and colleagues are now making MOFs even more versatile by demonstrating that the materials can be synthesized with protein centers (J. Am. Chem. Soc. 2015, DOI: 10.1021/jacs.5b07463).

The researchers engineered human ferritin with metal-binding sites, permitting each protein molecule to accommodate eight zinc ions on its surface. When the engineered protein is mixed with zinc and benzenehydroxamic acid, zinc binds to the protein and benzenehydroxamic acid acts as a linker, chelating zinc ions on separate ferritins. This self-assembly process results in a MOF crystal in which each zinc-decorated ferritin is linked to eight neighboring ones.

In addition to creating a new type of MOF, the work “introduces a new strategy for the rational design of protein crystals,” Tezcan says. Self-assembling protein networks have been created before, but earlier structures were made from two independent components instead of three and formed random structures instead of crystalline ones. The addition of a third component adds design versatility to the materials, and crystals are more uniform and well-defined than noncrystalline substances. Chemists have made MOFs with amino acids or short peptides, but never before with a functional protein such as ferritin, which acts in the body to store iron.

“The material couples the ability to design, fine-tune, and crystallize MOFs with the chemical and structural diversity of proteins,” says MOF expert Omar Yaghi of the University of California, Berkeley. “By placing proteins as structural elements into MOFs, one fixes them in position to serve as addressable entities for reactions and controlled dynamics.”

Seong Huh of Hankuk University of Foreign Studies, in Yongin, South Korea, says, “This is a unique approach to immobilize functional proteins into an inorganic matrix.” Huh and Seongsoon Park of Sungshin Women’s University, in Seoul, created an earlier protein-modified MOF. They think the new MOF could be useful for protein drug delivery, new types of biocatalysts, and molecular electronic devices.

But Huh notes that it remains to be seen if other proteins can form crystalline protein-MOFs as readily as ferritin. The metal-binding protein is roughly spherical, making it more amenable to crystallization than less symmetrical proteins.

Manuel A. Navia of Oxford Bioscience Partners, who developed and commercialized cross-linked enzyme crystals, agrees that the ferritin-based MOF “may be a special case and the global exploitation of the protein-MOF concept may be difficult.”