The self-assembly of proteins into higher-order superstructures is ubiquitous in biological systems. Genetic methods comprising both computational and rational design strategies are emerging as powerful methods for the design of synthetic protein complexes with high accuracy and fidelity. Although useful, most of the reported protein complexes lack a dynamic behavior, which may limit their potential applications. On the contrary, protein engineering by using chemical strategies offers excellent possibilities for the design of protein complexes with stimuli-responsive functions and adaptive behavior. However, designs based on chemical strategies are not accurate and therefore, yield polydisperse samples that are difficult to characterize. Here, we describe simple design principles for the construction of protein complexes through a supramolecular chemical strategy. A micelle-assisted activity-based protein-labeling technology has been developed to synthesize libraries of facially amphiphilic synthetic proteins, which self-assemble to form protein complexes through hydrophobic interaction. The proposed methodology is amenable for the synthesis of protein complex libraries with molecular weights and dimensions comparable to naturally occurring protein cages. The designed protein complexes display a rich structural diversity, oligomeric states, sizes, and surface charges that can be engineered through the macromolecular design. The broad utility of this method is demonstrated by the design of most sophisticated stimuli-responsive systems that can be programmed to assemble/disassemble in a reversible/irreversible fashion by using the pH or light as trigger.

The custom design of protein–dendron amphiphilic macromolecules is at the forefront of macromolecular engineering. Macromolecules with this architecture are very interesting because of their ability to self‐assemble into various biomimetic nanoscopic structures. However, to date, there are no reports on this concept due to technical challenges associated with the chemical synthesis. Towards that end, herein, a new chemical methodology for the modular synthesis of a suite of monodisperse, facially amphiphilic, protein–dendron bioconjugates is reported. Benzyl ether dendrons of different generations (G1–G4) are coupled to monodisperse cetyl ethylene glycol to form macromolecular amphiphilic activity‐based probes (AABPs) with a single protein reactive functionality. Micelle‐assisted protein labeling technology is utilized for site‐specific conjugation of macromolecular AABPs to globular proteins to make monodisperse, facially amphiphilic, protein–dendron bioconjugates. These biohybrid conjugates have the ability to self‐assemble into supramolecular protein nanoassemblies. Self‐assembly is primarily mediated by strong hydrophobic interactions of the benzyl ether dendron domain. The size, surface charge, and oligomeric state of protein nanoassemblies could be systematically tuned by choosing an appropriate dendron or protein of interest. This chemical method discloses a new way to custom‐make monodisperse, facially amphiphilic, protein–dendron bioconjugates.

Protein oligomers are ubiquitous in nature and play an essential role in various biological processes. Recently, there is an enormous interest to custom‐make synthetic protein oligomers through the bottom‐up approach. In this regard, genetic methods have made tremendous progress in the last decade. In comparison, only few chemical methods currently exist for this purpose. Herein, we report a modular synthetic strategy for the design of facially amphiphilic globular protein‐synthetic peptide conjugates. The self‐assembly of these bioconjugates is driven by strong hydrophobic interaction of the peptide domain. The size, molecular mass and oligomeric state of semi‐synthetic protein complexes strongly depend on size and surface charge of a globular protein as well as the length of the hydrophobic peptide domain. A systematic structure‐property relationship study of these semi‐synthetic proteins should shed more light on the understanding of various non‐covalent forces, which governs the oligomerization processes of naturally occurring proteins.

The design of well-defined monodispersed selfassembling semi-synthetic proteins is emerging as a promising research avenue. These proteins hold great potential to be used as scaffolds for various protein nanotechnology applications. Currently, there are very few chemical methods reported; however, they suffer from elaborate multistep organic synthesis. Herein, we report a new chemical methodology for the rapid synthesis of a diverse set of semi-synthetic protein families, which include protein amphiphiles, facially amphiphilic protein−dendron conjugates, and pH-sensitive protein−dendron conjugates. This chemical method holds great potential to access a wide variety of semi-synthetic proteins in a short time.

Self‐assembly of a monomeric protease to form a multi‐subunit protein complex “proteasome” enables targeted protein degradation in living cells. Naturally occurring proteasomes serve as an inspiration and blueprint for the design of artificial protein‐based nanoreactors. Here we disclose a general chemical strategy for the design of proteasome‐like nanoreactors. Micelle‐assisted protein labeling (MAPLab) technology along with the N‐terminal bioconjugation strategy is utilized for the synthesis of a well‐defined monodisperse self‐assembling semi‐synthetic protease. The designed protein is programmed to self‐assemble into a proteasome‐like nanostructure which preserves the functional properties of native protease.