Protein‐Engineered Functional Materials
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REVIEW Engineered Proteins www.advhealthmat.de Protein-Engineered Functional Materials Yao Wang, Priya Katyal, and Jin Kim Montclare* temperature, pH, or ionic strength. These Proteins are versatile macromolecules that can perform a variety of functions. triggers can further modulate the design In the past three decades, they have been commonly used as building blocks to and synthesis of novel biomaterials with generate a range of biomaterials. Owing to their flexibility, proteins can either increasingly complex functions. Because of their versatile nature, proteins can be be used alone or in combination with other functional molecules. Advances combined with a variety of other materials in synthetic and chemical biology have enabled new protein fusions as well as to create materials with novel functionali- the integration of new functional groups leading to biomaterials with emergent ties. Additionally, the inherent property of properties. This review discusses protein-engineered materials from the per- proteins to self-assemble has paved the spectives of domain-based designs as well as physical and chemical approaches ways to generate new protein assemblies. By precisely controlling the self-assembly for crosslinked materials, with special emphasis on the creation of hydrogels. of proteins, novel architectures with Engineered proteins that organize or template metal ions, bear noncanonical improved functional properties can be amino acids (NCAAs), and their potential applications, are also reviewed. designed.[3] The increasing interest in self-assembly of proteins has contributed significantly to 1. Introduction the development of biomaterials. These self-assembled protein based materials have a wide range of biomedical applications in Proteins are multifunctional macromolecules that regulate tissue engineering, biosensors, drug delivery, medical imaging, a number of biological processes and pathways.[1,2] With the gene therapies and protein therapeutics.[4–10] The properties of recent advances in protein engineering including synthetic proteins can be dynamically regulated by the organization or and chemical biology, new variants have been designed with templation of inorganic metal ions and more recently by intro- improved or novel functionalities. The diverse properties of ducing noncanonical amino acids (NCAAs).[11,12] proteins make them excellent candidates for building new bio- In this review, we highlight various recombinant proteins materials. Over the past few decades, continuous efforts have with a particular focus on their ability to assemble into various been made to develop protein engineered materials, capable of structures. In the following sections, we discuss functional replacing synthetic polymers, owing to their biocompatible and materials from the perspectives of domain-based designs as biodegradable properties.[1] well as physically and chemically crosslinked materials, with There are several advantages associated with the use of special emphasis on the design of hydrogels. In addition, we protein-based materials. The proteins can undergo conforma- review protein engineered materials bearing sequences for tional changes based on external stimuli, such as changes in metal crystallization and noncanonical amino acids, and their potential applications. Y. Wang, Dr. P. Katyal, Prof. J. K. Montclare Department of Chemical and Biomolecular Engineering New York University 2. Domain-Based Protein Engineered Materials Tandon School of Engineering Brooklyn, NY 11201, USA 2.1. Single Domain Protein Engineered Materials E-mail: [email protected] Prof. J. K. Montclare Single domain protein engineered materials are comprised of Department of Chemistry sequences that are derived from a single protein conformation. New York University While the sequences of single domain protein may vary with sim- New York, NY 10003, USA ilar or different repeats, the conformation of the domain remains Prof. J. K. Montclare Department of Biomaterials singular. In this section, we describe such single domains that New York University College of Dentistry can interact with each other to form hydrogel networks. New York, NY 10010, USA Prof. J. K. Montclare Department of Radiology 2.1.1. Elastin New York University School of Medicine New York, NY 10016, USA Elastin is a major component of the extracellular matrix The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adhm.201801374. (ECM) that directly impacts the elasticity of blood vessels and overall movement of joints and limbs.[13] Inspired by the DOI: 10.1002/adhm.201801374 natural protein, tailor-made elastin-like polypeptides (ELPs) Adv. Healthcare Mater. 2019, 8, 1801374 1801374 (1 of 33) © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advhealthmat.de Yao Wang was born in Beijing, China, and holds a bachelor’s degree in polymer materials. In 2015, she finished her M.S. in materials science and engineering at the University of Florida. The same year in September, she joined New York University Tandon School of Engineering where she is currently pur- suing her Ph.D. in materials chemistry. Her work focuses on patternable environmen- tally responsive hydrogels derived from protein tri-block copolymers for biomedical applications. Priya Katyal completed her Ph.D. in pharmaceutical sciences from the University of Connecticut, where she investigated protein–protein and protein–polymer interac- Figure 1. Plot showing the inverse phase transition of ELPs. Reproduced tions using biophysical and [14] with permission. Copyright 2014, John Wiley and Sons. biochemical approaches. She is a postdoctoral fellow in consisting of pentapeptide sequences have been investigated Professor Montclare’s lab at for their remarkable elasticity and self-assembling properties New York University, Tandon [14] (Figure 1). These properties render ELPs useful for applica- School of Engineering. Her tions in tissue engineering,[15,16] as drug delivery systems,[17–19] research is focused on developing self-assembled inject- and as probes for bioimaging applications.[16,20,21] able hydrogels for post-traumatic osteoarthritis. ELPs are comprised of a pentapeptide sequence, Val-Pro- Gly-Xaa-Gly or (VPGXG) , where ‘Xaa’ is an interchangeable n Jin Kim Montclare is a pro- amino acid (except proline) and “n” is the number of repeating fessor in the Department of units; the properties of ELPs can be tuned by varying Xaa or n Chemical and Biomolecular (Table 1).[16,22] The glycine and proline residues of ELPs main- Engineering at NYU Tandon tain the structure and function of elastin. ELPs exhibit a unique School of Engineering. lower critical solution temperature (LCST), which is also She has appointments referred to as the inverse transition temperature (T ); below t in biochemistry at SUNY their T , ELPs are soluble in aqueous solution and as the tem- t Downstate Medical Center, perature increases beyond T , ELPs undergo phase separation t chemistry at NYU, radiology and form aggregates.[23] Introduction of hydrophobic residues at NYU School of Medicine, at the “Xaa” position decreases T while ionic and polar residues t and biomaterials at NYU increase T . By varying the guest residue, it is possible to tune t College of Dentistry. Professor the ELP transition temperature from 0 to 60 C.[24,25] ° Montclare is performing groundbreaking research in The transition temperature of ELPs is also influenced by engineering proteins to mimic nature and, in some cases, their amino acid sequence, chain length, buffer concentration, work better than nature. She exploits nature’s biosyn- and polypeptide concentration.[26] Chilkoti and co-workers have thetic machinery and evolutionary mechanisms to design designed ELPs that form injectable depots capable of providing new artificial proteins. Her lab focuses on two research sustained release of peptide therapeutics.[22] Additionally, ELP areas: 1) developing protein biomaterials capable of self- solution when mixed with chondrocytes, result in the formation assembling into supramolecular structures and 2) engi- of coacervates that can maintain the cell viability (Figure 2a).[27] neering functional proteins/enzymes for particular The Chilkoti group has precisely tuned the T by varying the t substrates with the aim of targeting human disorders, drug guest residue and ELP chain length (Figure 2b) using recom- delivery and tissue regeneration. binant DNA techniques.[28] They have proposed a model that can predict the Tt of ELPs (Table 1) with the sequence repeats of VPGVG and VPGAG across a range of molecular weights and The Conticello group has generated different types of BAB chain lengths.[28] These studies have allowed the design of new (Table 1) elastin-based triblock protein polymers, capable of ELPs for applications in medicine and biotechnology.[22,26] forming thermoplastic elastomer hydrogels (Figure 3).[29,30] Adv. Healthcare Mater. 2019, 8, 1801374 1801374 (2 of 33) © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advhealthmat.de Table 1. Sequences of single domain proteins. Type of protein Name of protein Sequence Reference Elastin Protein Elastin Like Proteins (VPGVG)n [24] (ELPs) (VPGAG)n[(VPGIG)2(VPGKG)(VPGIG)2] [16] [139] [MSKGPG-(XGVPG)n-Y or WP] [26] ELP[V5A2G3] -n [28] ELP[V1A8G7] -n ELP[V5]-n *n = length of the pentapeptide BAB Thermoplastic Two BAB sequences: [30] Elastomer Hydrogels VPAVG[(IPAVG)4(VPAVG)]16IPAVG}-[VPGVG[(VPGVG)2VPGEG(VPGVG)2]30VPGVG]{VPAVG[(