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WIREs Nanomed Nanobiotechnol
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Rational protein design: developing next‐generation biological therapeutics and nanobiotechnological tools

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Proteins are the most functionally diverse macromolecules observed in nature, participating in a broad array of catalytic, biosensing, transport, scaffolding, and regulatory functions. Fittingly, proteins have become one of the most promising nanobiotechnological tools to date, and through the use of recombinant DNA and other laboratory methods we have produced a vast number of biological therapeutics derived from human genes. Our emerging ability to rationally design proteins (e.g., via computational methods) holds the promise of significantly expanding the number and diversity of protein therapies and has opened the gateway to realizing true and uncompromised personalized medicine. In the last decade computational protein design has been transformed from a set of fundamental strategies to stringently test our understanding of the protein structure–function relationship, to practical tools for developing useful biological processes, nano‐devices, and novel therapeutics. As protein design strategies improve (i.e., in terms of accuracy and efficiency) clinicians will be able to leverage individual genetic data and biological metrics to develop and deliver personalized protein therapeutics with minimal delay. WIREs Nanomed Nanobiotechnol 2015, 7:330–341. doi: 10.1002/wnan.1310 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies
Computational protein design scheme. A given protein can be decomposed into two structural classes: (i) backbone and (ii) amino acid sidechains. In a single‐state enzyme design calculation sidechains are incorporated on to a fixed‐backbone scaffold (follow the blue arrow and box). Each sidechain in the design goal (e.g., enzyme catalytic site) is allowed to assume any number of predefined conformations (i.e., rotamers). In turn, each amino acid pair is scored based on its interaction with other sidechains (and substrate in the case of enzyme design) producing a total energy score (Etotal). All pairwise interactions are recorded in a look‐up table and then optimized to identify the putative minimum energy for stability and optimal function. The design cycle is conducted in an iterative fashion (green feedback loop and yellow arrows). Innovations brought to bear in recent studies: To capture the scaffold feedbacks that may influence catalysis the Wilson research group has implemented a provisional discrete multistate design strategy [yellow arrows, also see the Designing Conditional Catalysis (A New Frontier) section below] to confer temperature‐adapted function in the adenylate kinase enzyme scaffold. The objective of this study was to implement and improve our ability to confer temperature‐adapted functions—setting the stage for other conditional functions, e.g., oxidative adaptation, see additional optimization inset. In addition, this work represents a significant attempt to understand enzyme scaffold allosteric feedbacks.
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Redesigned antibodies. (a) Immunosuppressants belatacept, abatacept, and novel analog Xpro9523 with enhanced binding to human CD80 and CD86, prevents T cell proliferation. (b) Designed antibody inhibitors for allergic and inflammatory reactions mediated via mast cells and basophils. Stimulation of mast cells and basophils via crosslinking of FcϵRI promotes degranulation, which leads to allergic and inflammatory reactions. Engineered fusion proteins mitigate FcϵRI crosslinking via the coengagement of FcγRIIB and FcϵRI.
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(a) Antibody schematic. (b) Flow chart for the production of catalytic antibodies. The process begins with the design of a transition‐state analog. Next the analog is typically injected into and animal to illicit antibody production; in principal, extraction of animal whole serum will contain polyclonal antibodies. To isolate monoclonal antibodies requires the extraction of spleen cells and merging them with an immortal cell line to produce hybridomas and antibodies can be subsequently isolated. Finally, generated antibodies can be improved via rational design.
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Designed enzyme therapeutics. (a) Designed catalysis to intercept organophosphate nerve agents. Nerve agents inhibit acetylcholinesterase via blocking native chemical signals (e.g., acetylcholine), resulting in cholinergic crisis. Prolong exposure to nerve agents can result in a phosphonylated enzyme (aged) that is resistant to treatment. Novel enzyme therapeutics aim to intercept and hydrolyse nerve agents, rendering the OP compounds impotent. (b) Individuals with Celiac disease consume foods containing gluten their immune system will produce antibodies to the immunogenic peptides produced for partially digested gluten proteins. Designed proteases have been produced to aid with the digestion of gluten proteins. (c) Designed nucleases that stimulate the process of homologous recombination, putative therapeutics for gene replacement. Engineered endonuclease promote rapid cleavage kinetics and production of 3′ overhangs upon cleavage, which can increase rates of homologous recombination.
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