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Chapter 7
Protein Self-Assembly: From Programming
Arrays to Bioinspired Materials
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Quan Luo, Tiezheng Pan, Yao Liu, and Junqiu Liu*
State Key Laboratory of Supramolecular Structure and Materials, College
of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012,
P. R. China
Natural protein assemblies are intriguing soft materials that
exhibit highly complex hierarchical structures and collective
properties for many important biological functions, which
make them difficult to mimic synthetically. This chapter
summarizes the recent advances in the research field of protein
assembly and highlights several innovative design strategies
for precise manipulation of proteins into extended-, periodic
arrays with desired morphologies. These artificially created
protein nano/microstructures allow for further functionalization
and serve as a versatile platform to create a wide variety of
biomaterials by coupling their well-defined architectures with
different functional groups, molecules, or nanoparticles for
diverse applications. Mimicking the structures and properties
of natural protein materials through hierarchical protein
self-assembly may help to unravel the complexity and diversity
of the protein aggregation process and develop a new generation
of biomimetic materials. This will provide a valuable source
of inspiration for future design of novel biomaterials and
accelerate its development towards high precision, efficiency,
and multifunctionality.
Natural soft materials, such as cellular membranes, the cytoskeleton and
surface shell/wall structures, are built in a mild environment via spontaneous
© 2017 American Chemical Society
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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organization processes (1–3). They are comprised of different biomarcomolecules
that form highly complex hierarchical architectures across multiple dimensions.
Proteins are one of the most versatile constituents, consisting of 20 standard
amino acids that can fold into a specific conformation to meet physiological
demands (4). Protein molecules not only function well alone, but also assemble
into exquisite superstructures for many important cellular functions (5). The
driving forces for the self-assembly process are multiple, weak non-covalent
interactions (6), which endow protein-based biomaterials with a large amount of
biological/chemical versatility through dynamically reversible regulation of their
collective properties for high performance and environmental adaptation (7).
Inspired by the elegance of nature’s bottom-up fabrication, the development of
artificially created protein assemblies presents an imminent challenge. This offers
a great opportunity to develop novel functional biomaterials through mimicry and
to gain valuable insights into biological assembly processes.
Since supramolecular techniques have emerged as a powerful method
for controlling molecular aggregation (8), the application of the principles
of molecular recognition opens up tremendous possibilities for small organic
molecules to design a wide variety of biomimetic nano/microstructures with
promising properties such as processability, self-healing, recyclability, and
stimuli-responsiveness (9, 10). However, the research field of direct manipulation
of protein self-assemblies is still in its infancy due to the structural complexity,
heterogeneity, and instability of protein molecules (11, 12). In addition, the
extremely rich biodiversity leads to limited knowledge of their underlying
assembly mechanism. Unlike small-molecule recognition, the high fidelity of
protein association relies on a more extensive binding interface that contains
complementary contacts to induce and stabilize the specific binding between
two protein subunits (13). How to precisely control the relative orientation and
multi-specificity of these complex building blocks is a key step in the construction
of biomimetic nano/microstructure.
The design protocol for dictating protein self-assembly is to employ genetic
engineering or site-specific chemical modification to introduce supramolecular
self-associating components at the protein interfaces, which attempt to control
or interfere with protein-protein recognition processes so as to achieve the
desired self-assembled architectures (14, 15). In addition, some experimentally
determined oligomeric protein domains were utilized as a connector to create
1D (e.g. nanowires), 2D (e.g. the layered structures), and 3D (e.g. cage-like
structures) periodic protein arrays through genetic fusion of them along the shared
symmetry axes (16). The overall geometries of these protein assemblies can be
predetermined by the intended relative orientation of neighboring pairs.
The intent of this chapter is to describe the recent developments in the
field of protein self-assembly. The strategies that drive protein recognition and
aggregation to construct highly ordered hierarchical superstructures have been
summarized. Furthermore, some typical examples are discussed with an emphasis
on the design principle, self-assembly process, characterization method, selective
modification, and surface functionalization. We hope these research details could
provide guidance for the future design of bioinspired protein nano/micromaterials
for a wide range of biomedical applications.
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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Proteins as a Building Block for Multidimensional
Naturally oligomeric protein domains provide a variety of basic building
blocks for self-assembly into multidimensional biomaterials. Depending on the
structural features, binding orientation and stoichiometric ratios, neighboring
protein subunits hold together in the formation of particular symmetric
superstructures to promote their biological functions (Figure 1) (17). For
example, collagen can be assembled into cross-striated microfibrils to provide
structural support for cells (18); S-layer proteins are known to form highly porous
self-assembled meshworks to enhance mechanical and osmotic stabilization (19);
viral capsids enable selective packaging of the genome into their tubular, globular,
or polyhedral nanostructures (20). These structure-function correlations give
important clues about the mechanisms behind how different protein components
accomplish recognition and aggregation, as well as collective properties and
functions under specific environmental conditions.
Figure 1. Natural protein assemblies with multidimensional superstructures. (a)
Linear collagen; (b) Planar S-layer (c,d) tubular and polyhedral capsids.
Initially, great efforts have been made to reproduce some complex protein
self-assembly processes in vitro for a better understanding of protein-protein
interactions (PPIs) and their underlying assembly principles, which may be helpful
for rational design and preparation of artificial protein assemblies. Typically,
virus systems such as the tobacco mosaic virus (TMV), cowpea chlorotic
mottle virus (CCMV), and bacteriophage φ6 have been studied to explore their
nucleation and growth processes (21–23). These bioinspired nanotechnologies
offer a facile and environment-friendly approach to develop large-scale protein
biomaterials. In this design, well-characterized oligomeric protein domains or
motifs can be employed to provide control over the relative orientation of the
fusion partners. Symmetry-matching fusion, peptide-mediated assembly, and
protein template-induced strategies are classified into this category.
Following the above-mentioned studies, de novo design of new protein
interaction surfaces made it possible to modulate the binding mode of existing
protein assemblies and to dictate the nonself-associating protein monomers
self-assembly into desired architectures (24). Several other strategies, such as
metal-coordination-driven strategy, electrostatic-interaction-induced strategy,
receptor-ligand interaction-directed strategy, host-guest recognition-driven
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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strategy, etc. allow the assembly design with greater structural complexity
and diversity through site-directed mutagenesis or chemical modification of
the relatively reactive groups on the protein surface to create completely new
PPIs (14). Although many biomimetic nano/microstructures have been built
successfully based on these strategies, how to duplicate the highly intricate
morphologies and unique properties of natural systems is still one of the most
difficult challenges. This will undoubtedly require a set of rational design rules
and a combination of two or more innovative strategies to generate more complex
protein assemblies with customized characteristics.
In fact, the ability to create sophisticated nano/microstructure is only a
first-step toward protein-based nanofabrication. The rapid development of this
field provides a rich source from which to design versatile functionalities. A
variety of specific groups, molecules, nanoparticles with chemical, electronic,
or photonic properties can be precisely positioned on artificially created
supramolecular protein scaffolds for further functionalization (25). Many
promising applications were realized by coupling highly ordered protein
superstructures with diverse functions of the modified components. On the other
hand, the well-ordered protein nano/microstructures offer the opportunity to
reinforce its innate capabilities via the favorable microenvironment formed by
self-assembly (15). The available protein assemblies often exhibit significantly
improved performance than that of the mixture of the monomeric forms, which is
an alternative way to import new function into self-assembled protein materials
with high efficiency.
In the following sections, we will present the most significant examples that
use different design strategies to create extended 1D, 2D and 3D protein arrays
with increasing size and complexity. By mimicking the structure and function
of natural protein assemblies, researchers have an unprecedented opportunity
to unravel the mystery behind their inherent properties of robustness, strength,
elasticity, adaptability, and multifunctionality. The challenge to translate these
bioinspired design concepts into improvements in biomimetic model systems
would bring practical benefits and be useful for application purposes.
Protein Self-Assembly To Create 1D Array
Fibrous protein materials (e.g. collagen, elastin, fibronectin, and laminin) are
commonly characterized by superior mechanical properties, which makes them a
promising biomimetic target for the design of biomaterials (26). Using nature’s
design principles as an inspiration, a variety of polymeric protein assemblies have
been generated by modular self-assembly of repeat protein units in a head-to-tail
or end-to-end manner.
Natural Self-Complementary Pairs To Induce Linear Protein Self-Assembly
The direct utilization of the symmetry characteristic of naturally oligomeric
protein domains or motifs is first considered as a reliable strategy for the
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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synthesis of protein nanowires. Rational alignment of a common symmetry axis
between neighboring building blocks can determine the gross morphology of a
protein assembly through highly specific, directional and strong interactions of
the pre-existing protein interface. An early example that uses the genetically
oligomeric fusion method to prepare protein filaments has been reported by the
Yeates’ group (27). The relative orientation between dimeric M1 matrix protein
and carboxylesterase can be controlled by a semi-rigid helical linker that holds the
two protein domains together via genetic fusion according to a particular design
rule that their symmetry axes do not intersect. As predicted, a self-complementary
dimer was formed at each terminus of the designed fusion protein and the iterative
dimerization resulted in the formation of large-scale linear protein homopolymer.
Transmission electron microscopy (TEM) analysis showed the presence of protein
filaments with a width of ~4 nm, which can further organize into higher-order
bundles or network structures to mimic the self-assembly processes of long fibers
found in Nature.
Instead, some stable and reliable protein folding motifs can be fused to the
N/C-terminus of target proteins to induce protein-protein association. As we
know, secondary structures such as α-helices are the elementary units of natural
protein domains, a few of which can be accurately predicted and designed to
achieve the intended interaction specificity. The combinatorial design rules of
amino acids in the peptide sequences allow for more diverse and minimized
interactions as the driving force to drive protein self-assembly. Thus, genetic
engineering of a short α-helical peptide into proteins opens up a new possibility
to control nonself-associating protein dimerization via coiled-coil interactions.
This strategy has been successfully applied to construct a series of heteroor homodimeric functional protein complexes (28, 29). Subsequent research
has demonstrated that coiled-coil-mediated self-assembly was able to fabricate
larger-scale linear polyprotein chains when the protein units were difunctionalized
with two coiled-coil binding partners at both of its termini. For instance, Rief et
al. prepared a protein-peptide fusion domain that contained Ig27 protein flanked
by two 35-amino acid coiled-coil polypeptide (LZ10) (30). The strong binding
between homodimeric LZ10 connected I27 domains to ensure the head-to-tail
parallel orientation, and this interaction was further enhanced by incorporating a
cysteine residue at a proper site in the LZ10 sequence to stabilize the coiled coil
via disulfide bond formation. Size-exclusion chromatographic analysis confirmed
that more than 30 coiled coil linked Ig27 monomers were assembled to form
the polymeric protein chains. The mechanical properties of individual chains
were examined by atomic force microscopy (AFM), in which the unzipping
and overstretching transitions of a single coiled coil occurred at 10 pN and 25
pN respectively when exposed to a stretching force. These findings revealed
the potential of coiled coil motifs in supramolecular polymerization of protein
molecules for developing soft fibrous biomaterials with high elasticity and
Nature has also inspired the development of other self-complementary
pairs for protein multimerization based on metal coordination, sequence-specific
dsDNA recognition, intermolecular disulfide linkage, and receptor-ligand
interaction. Incorporation of a certain metal-ligand pair on the surface of proteins
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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offers the advantage of strength and directionality to induce linear protein
self-assembly. Bis-His is the most famous surface chelating motif that has the
ability of selective metal binding under controlled environmental conditions.
Liu et al. designed a C2-symmetric homodimeric enzyme, His(6)-tagged
glutathione-S-transferase (GST), as the building block for the coordination-driven
supramolecular polymerization (31). In the presence of Ni2+ ions, two His(6)-tag
arms on the opposite side of GST provide high-affinity metal binding sites
for supramolecular coordination that creates de novo PPIs to induce protein
recognition in the formation of 1D protein nanowires (Figure 2a). Because of
the microenvironment formed by enzyme arrays, a substrate may be more easily
accessible to the active centers, which cause a slight increase in enzyme activities
for metal-directed protein assemblies as compared with enzyme monomers.
Moreover, the assembly and disassembly behavior of this system can be reversibly
regulated by the pH-dependent dimerization of GST, which may help to inspire
further design of “smart” protein materials in response to environmental changes.
Figure 2. (a) Incorporation of His(6)-tag into GST for Ni2+-induced linear
self-assembly; Adapted with permission from reference (31). Copyright 2012
Royal Society of Chemistry. (b) Coassembly of dimeric ENH protein and dsDNA
into linear structures. Adapted with permission from reference (32). Copyright
2015 Nature Publishing Group. (c) Linear hemoprotein polymerization induced
by heme-hemeprotein interactions. Adapted with permission from reference (36).
Copyright 2007 American Chemical Society.
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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On the basis of protein-DNA recognition, linear co-assembling nanostructure
was obtained by combining the two molecule types into one biomaterial (32). In
this case, computational protein design has been used to optimize an energetically
favorable interface on Drosophila Engrailed homeodomain (ENH) for C2
symmetrical homodimerization. The designed variant dualENH has a dsDNA
binding site on its outward faces to recognize specific DNA sequences, and thus
the growth direction of protein-DNA arrays mainly relies on the positioning of
protein-binding sites on the dsDNA. By creating two protein-binding sites parallel
to the horizontal axis of dsDNA, a nanowire with a width of 15 nm and a length
of 300 nm was spontaneously formed by mixing the protein and dsDNA building
blocks (Figure 2b). Atomic force microscopy (AFM) images showed the size and
shape of highly ordered 1D protein-DNA architecture, the polymerization degree
of which was estimated to be approximately 60 units based on the design model.
Additionally, engineered DNA structures such as aptamers can be designed for
protein recognition to achieve the linear arrangement. For example, Willner’s
group synthesized a bisaptamer, a β-aptamer at the 3′ end and an α-aptamer at
the 5′ end, for self-assembly into linear DNA-thrombin nanostructures via 1:2
binding of two different domains on thrombin (33). These hybrid biomaterials
can integrate the physical/chemical nature of two components, which allows the
materials design to develop towards greater functionality.
Intermolecular disulfide bond formation offers a new opportunity for
self-assembly of more robust 1D protein materials. Cysteine-modified protein
variants are easy to connect linearly under oxidizing condition via a disulfide bond
due to its desirable properties of high stability at low pH, long bond-distance and
restricted dihedral angle compatible with local protein confirmation. Ballister and
co-workers demonstrated the success of this design concept to construct a protein
nanotube. The ring-shaped Hcp1 protein was engineered with cysteines on the top
and bottom faces for covalent stabilization of ring-ring stacking in a head-to-tail
fashion via the formation of disulfide linkages (34). Further studies revealed that
the disulfide-stabilized Hcp1 nanotubes display a unique combination of two
distinctive properties: covalent strength and redox-controlled assembly behavior.
This feature is an obvious advantage in developing protein-based nanocapsules
for controlled drug delivery when Hcp1 nanotubes were functionalized with
polyamidoamine (PAMAM) dendrimer as the plug component via thiol-maleimide
reaction. A similar strategy can be applied to another protein system, 11-mer
cyclic thermostable TRAP (35). Two mutations V69C and E50C on opposite
faces of TRAP ring result in supramolecular polymerization of them into long
nanotubes and further self-assembly into micro-sized bundles. The nematic
alignment of high-density TRAP nanotubes is similar to the liquid crystalline
structure of microtubules. Insights into the self-assembly mechanism of this
artificial soft material may be an important step to improve our understanding of
complex microtubule dynamics in vitro.
Protein receptor-ligand pairs have evolved to bind with very high affinity
and selectivity, which provides a powerful tool to modulate protein self-assembly
to form nanofibers. The strategy to control the head-to-tail assembly orientation
can be realized by using a chemically linked ligand to induce protein association.
In principle, the design accuracy and diversity is supposed to be guaranteed
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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by reliable interprotein interactions and distinct synthetic ligands. As a
proof-of-concept, the strong hemoprotein-heme interactions was first explored
by Hayashi’s group for supramolecular polymerization of hemeproteins (Figure
2c) (36). A single H63C mutation was introduced at the cytochrome b562 surface
opposite to the heme pocket to react with an iodoacetamide-linked heme for
preparing a covalently heme-attached hemoprotein. The fibrous protein arrays
were achieved by successive heme-mediated interprotein interactions to obtain
an appreciable polymerization degree of approximately 20 units, which exhibited
an obvious linker length-dependent increase in size distribution. Following the
feasibility of this strategy, the same group extended their investigations to another
heme-binding protein, myoglobin (Mb) (37). In this case, it is not necessary to
perform any chemical modification on protein surfaces to influence its structural
and functional integrity. The synthetic heme dimers or heme-bis(biotin) dyads
have proven to be effective in dictating disulfide-bond-linked Mb into polymeric
chains without impairing their bioactivity (37, 38). This will lead to the future
development of new functional biomaterials with electron-transfer, O2-binding,
or enzymatic properties.
Chemically Controlled Self-Assembly of Proteins into Linear Structures
Besides the natural pairs mentioned above, chemically synthetic pairs
have also attracted increasing attention in the construction of fibrous protein
assemblies. Some macrocyclic molecules, such as cyclodextrins (CDs) and
cucurbit[n]urils (CB[n]), contain central hydrophobic cavities ringed with
multiple binding sites for selective inclusion of guest molecules in their interiors,
analogous to the specific interactions in biological systems. Using the strategy
based on these artificially created pairs, the high stability, reversibility, and
responsiveness can be realized in a “head-to-tail” self-assembling protein
system, which enables us to control material properties and functions by
manipulating host-guest recognition-driven protein assembly.
et al. pioneered the use of strong host-guest pairs (e.g. β-CD/ lithocholic
acids (LAs), CB[8]/tripeptide phenyalanine-glycine-glycine (FGG), and
CB[8]/methylviologen (MV)/naphthalene (Np)) for chemically induced protein
dimerization (39–41). All the selected pairs were featured with a high equilibrium
association constant (Kd > 1 x 10-6 M) to ensure the specific binding between two
protein units. As evidence of functional protein modulation, their recent work
demonstrated that enzymatic activity can be switched by selective and reversible
dimerization of a split-luciferase heterocomplex using the CB[8]/FGG pair (42).
Beyond dimerization, the binding strength of CB[8]/FGG pair allows for the
design of 1D protein nanowires by N-terminal fusion of dimeric GST with FGG
for a CB[8]-mediated protein assembly (Figure 3a) (43). Furthermore, the fusion
of a Ca2+-responsive recoverin into GST can further transform these biomaterials
into a protein nanospring to mimic the elastic motions of natural muscle fiber (44).
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Figure 3. (a) CB[8] induced self-assembly of GST-FGG into nanowires based
on host-guest interactions; Adapted with permission from ref (43). Copyright
2013 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim. (b) Positively charged
QDs to drive the self-assembly of negatively charged SP1 into nanotubes via
electrostatic interactions. Adapted with permission from ref (45). Copyright
2014 American Chemical Society.
The chemically synthetic nanoparticles with charged surfaces offer a
long-range driving force to stabilize protein interfaces for controlled arrangement
of linear protein arrays. This strategy is easy to implement, but needs to carefully
consider the steric geometric design and charge distribution on protein surfaces.
Typically, the ring-like stable protein one (SP1) covered with a high density of
negatively charged residues on the top and bottom faces was selected as the
building block for electrostatic self-assembly (45). Only the positively charged
quantum dots (QDs) with the size fitted for the central hole of SP1 nanoring
is capable of inducing the self-assembly of proteins into highly ordered 1D
nanowires via electrostatic interaction and spatial complement (Figure 3b).
The design principle is also applicable to other positively charged globular
nanoparticles, such as core-cross-linked micelles (CCMs) and fifth-generation
poly(amino amine) (PAMAM) (46, 47). As visualized by TEM characterization,
the nanoparticles were laid on both sides of each SP1 protein in a sandwich
arrangement, which provided optimal scaffolds to incorporate different functional
molecules (e.g. chromophores and synergistic GPx-SOD enzyme system)
for extending the applications of protein nanowires for biosensors, catalysis,
and pharmaceuticals. Furthermore, ethylenediamine (EDA) and carbodiimide
(EDC)/N-hydroxyl sulfosuccinimidyl (sulfo-NHS) can serve as an electrostatic
inducer and crosslinking agent for selective conjugation of its amino groups with
the carboxyl groups of SP1 to promote the strength of protein assemblies (48).
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The “zero-length” crosslink offers a distance constraint for assembly refinement
to yield more stable and uniform protein nanowires, which might have greater
value for future applications.
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Molecular-Level Control for Multi-Dimensional Protein Arrays
Linear protein arrays are relatively simple assemblies, which lack the
structural complexity for exploration of advanced biomaterials. Rational design
and control of interprotein interactions by surface-attached functional groups at
the molecular-level are able to change the order and orientation of the protein
self-assembly process. The combination of high pre-existing symmetry of protein
building blocks with external control further expands 1D nano/microsturcture to
higher dimensional architectures. In some cases, the mechanisms that govern
their growth sizes and morphologies can be quantitatively analyzed and then
applied to guide the facile creation of periodic 2D and 3D protein arrays. This
progress may help address fundamental principles about the structural diversity
and shed light on some important biological assembly processes.
Protein Self-Assembly To Create Cyclic and Tubular Arrays
Cyclic protein assemblies are key intermediates in the modulation of
microtubule nucleation phase by providing spatial and temporal control over
the initiation of its growth. The molecular details are currently being revealed
by studying supramolecular protein polymerization and macrocyclization in
vitro. Wagner et al. synthesized a dimeric methotrexate (bisMTX) to induce
the self-assembly of peptide-linked dihydrofolate reductase (DHFR) into highly
stable ring-like structures through its intrinsic MTX-binding ability (49).
Dynamic light-scattering (DLS) and TEM data supported the formation of protein
nanorings, whose sizes are tunable between 8 and 20 nm by varying the length
and composition of the peptide linker (Figure 4a). Also, the strength of bivalent
ligand-mediated PPI is a critical factor to regulate energetics and geometry of
protein self-assembly for ring formation. This design principle was validated by
Meijer’ group using SEC and quadrupole time-of-flight (Q-TOF) mass analysis
when ribonuclease S-protein and S-peptides were chemically connected via a
flexible oligo(ethylene glycol) (EG) linker to construct cyclic protein oligomers
based on their strong and directional noncovalent interaction (50). In fact,
there existed an equilibrium between cyclic and linear products, which was
thermodynamically controlled by the ring-chain competition mechanism under
a critical concentration. Therefore, the related design criteria can be established
to meet the requirements for future fabrication of either cyclic or linear protein
chains in a predictable way. Furthermore, the formation of antibody nanorings
were highly favored by fusion of an anti-CD3 single-chain variable fragment
(scFv) to DHFR, which leads to an opportunity for developing targeted cellular
delivery system through a third arm containing bis-MTX functionalized with
toxic proteins or oligonucleotides for therapeutic purposes (51).
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Figure 4. Supramolecular protein polymerization and macrocyclization. (a)
DHFR nanoring formed by BisMTX-induced self-assembly; Adapted with
permission from ref (49). Copyright 2006 American Chemical Society. (b,c)
Cooperative self-assembly of GST and SBA into cyclic and tubular structures.
Adapted with permission from ref (52) and (54). Copyright 2013 and 2016
American Chemical Society.
Another type of cyclic protein polymerization was accomplished by
cooperative interactions. One representative work was reported by Liu et al.,
who utilized the metal-coordination and protein-protein interactions to control
over the assembly orientation based on rational steric protein design (52). The
V-shaped configuration of two bis-His chelating sites on the engineered GST
dimers endeavors to maintain a proper molecular curvature for macrocyclization,
which was further reinforced and stabilized by the cooperative effect of multiple
noncovalent interactions to determine the final architectures (Figure 4b). The
design protocol was demonstrated to be feasible for another protein system, M13
bacteriophage (53). Two genetic modifications at each end of filamentous M13
viruses are able to create a protein building block with anti-streptavidin peptide
and His(6)-tag. M13 virus-based ring structures were formed by cooperative
protein self-assembly using a heterobifunctional linker that contains tetrameric
streptavidin (STV) and Ni(II)-nitrilotriacetic acid complex (NiNTA) for selective
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interconnection of dual-end modified viruses via peptide/STV interactions and
metal coordination. Inorganic materials such as ZnS, CdS, or FePt with optical,
electronic, or magnetic properties can be crystallized into these virus-based ring
scaffolds for designing functional devices when the nucleating peptides were
displayed on the major coat protein VIII (pVIII). Very recently, this strategy has
also proven to be successful in the construction of large-scale artificial protein
microtubules (54). The synthetic hetero-ligand with both sugar and rhodamine
B (RhB) moieties, provided synergistic dual driving forces, protein-sugar
interactions and π-π stacking, to induce the self-assembly of tetrameric soybean
agglutinin (SBA) into periodic helical arrays that wind together to form a
26 nm-wide hollow tubular structure (Figure 4c). Circular dichroism (CD)
spectroscopy and cryo-electron microscopy (cryo-EM) analyses indicated a
pseudo-1D microtube growth mechanism that the helical protofilament might be
a crucial intermediate for microtube formation.
Protein Self-Assembly To Create Planar or Branched Network
The structural extension can be increased by exploring new self-assembling
components and more complex designs. Multi-arm or branched building blocks
were designed to introduce symmetry into protein assembly to generate 2D
planar or branched network by accurate control of molecular stoichiometries
and orientation. As an early example, tetrameric L-rhamnulose-1-phosphate
aldolase (RhuA) was modified with two cysteines in each subunit to prepare a
four-arm junction (bR) that connects eight biotins on its surface via thiol-disulfide
exchange reaction (55). The quadratic network was produced by self-assembly
of two biologically unrelated proteins, C4-symmetric bR and D2-symmetric STV,
based on the strong binding affinity between biotin and streptavidin. In fact,
the design can be simplified to use the symmetry-matching fusion method to
create distinct protein “bricks” with multiple connection points through genetic
fusion of oligomeric protein subunits with matching rotational symmetries.
Noble et al. employed this principle to design planar protein lattices using
appropriate point group symmetry combination by manipulating the geometry
and flexibility of the linker within fusion proteins (Figure 5a) (56). These
well-ordered 2D protein arrays can be further fused with functional protein
components to capture nanoparticles and thus provides a stable framework
to manufacture biomaterials with diverse properties. On the other hand, the
design and synthesis of multivalent ligands with geometric control also makes
a significant contribution to the structural diversity of protein assemblies. By
adding a novel heme triad as a pivot molecule, supramolecular linear hemoprotein
assemblies mentioned above converted fully into 2D protein networks (Figure 5b)
(57). One possible mechanism is that a “Y-shaped” trident node was first formed
and then grew along its terminal direction via heme-heme pocket interactions to
yield highly branched chain structures. This strategy greatly reduces the need
for geometrically specific protein building blocks and shows great potential for
fabrication of more complicated structures.
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Figure 5. (a) Planar protein lattices created by self-assembly of
ALAD-STV/Streptag I fusion proteins with matching rotational symmetry;
Adapted with permission from ref (56). Copyright 2011 Nature Publishing Group.
(b) The formation of the hemoprotein network assembly via heme-heme pocket
interactions using a heme triad as a pivot; Adapted with permission from ref (57).
2012 Royal Society of Chemistry. (c) Linear and S-shaped thrombin patterns on
self-assembled DNA tile scaffolds via biotin-STV interactions. Adapted with
permission from ref (60). Copyright 2007 American Chemical Society.
A more general and powerful approach to produce large 2D protein assemblies
is the utilization of naturally evolved or artificially synthetic nano/microstructures
as templates to organize proteins. S-layers are highly porous protein meshwork
on cell surface. The unique self-assembly feature enables S-layer proteins to form
mono- or double layers in solution for high-density display of foreign proteins
to produce patterned films. According to this principle, a variety of functional
proteins such as streptavidin, antibodies, glycoprotein, fluorescent protein, and
enzymes can be fused to S-layer proteins at the N- or C-terminal positions
and then self-assembled into geometrically well-defined protein layers. More
importantly, the periodic arrangement of functional proteins combined with their
biological activities offer a unique way to design high-performance biomaterials
such as biosensors, vaccines, biomarkers, biocatalysts, and biodetectors. For
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
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instance, the formation of S-layer nanostructures difunctionalized with methyl
parathion hydrolase (MPH) and anthrax-specific antibodies not only increased the
enzymatic stability, but also achieved higher anthrax-detection sensitivity than
that of monomeric fusion proteins (58). This finding is regarded as a powerful
evidence for coupling the intrinsic biological functions and superstructures of
protein assemblies with significantly improved properties in early serological
diagnosis of anthrax disease.
Figure 6. (a) Self-assembly of WA20-foldon fusion proteins into different
polyhedral using “Nanohedra” design rule; Adapted with permission from
ref (61). Copyright 2015 American Chemical Society. (b) Self-assembly of
KDPGal-FkpA fusion protein into a cube-shaped cage through symmetry
manipulation; Adapted with permission from ref (62). Copyright 2014 Nature
Publishing Group. (c) Computational design of self-assembled protein cages
with tetrahedral or octahedral point group symmetries; Adapted with permission
from ref (64). Copyright 2014 Nature Publishing Group. (d) Metal-directed
self-assembly of proteins into 1D nanotubes, 2D and 3D planar arrays via
thermodynamic control. Adapted with permission from ref (66). Copyright 2012
Nature Publishing Group.
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The self-assembly of more diverse 2D protein arrays have been achieved
by using abundant DNA nanostructures as templates due to their precise
positional control. Many crossover DNA tiles, such as double-crossover
molecules (DX), triple crossover molecules (TX), 2-, 4-, and 6-helix bundles, and
cross-shaped tiles with sufficient stability and rigidity, are capable of forming
large superstructures according to the number, orientation, and layout of the
crossover pairs, which allow their use in the immobilization of target proteins
into desired architectures. The LaBean group designed a biotin-labeled 4 × 4
DNA tile with sticky-ended cohesions for self-assembly of uniform 2D nanogrids
with periodic square cavities (59). A single flat protein layer was formed by
templated self-assembly of streptavidin onto the tethering sites of DNA nanogrids
via strong streptavidin-biotin binding. Furthermore, self-assembly of DNA
tiles can be reprogrammed by varying the sticky ends to control the final DNA
lattice morphologies, leading to more sophisticated protein arrays for some
practical applications. Moving forward, using a set of four DX molecules, Yan
and co-workers were able to create the desired geometrical protein pattern on
rectangular-shaped DNA nanoarrays (60). In this case, two protein-binding
aptamer sequences were incorporated into different tiles at specific positions
of DNA nanostructures for capturing growth factor and thrombin in the
construction of linear and S-shaped protein patterns (Figure 5c). Taking advantage
of the sequence specificity and the resulting spatial addressability of DNA
nanostructures, this design principle could be further extended to achieve any
assembled architectures by precise arrangement of proteins at predetermined
3D Self-Assembly Design for Greater Structural Complexity and Diversity
Although 2D protein arrays represent a significant progress toward
controllable protein assembly, the development of complex 3D structures to reach
higher levels of control and functionality remains a considerable challenge. Not
only the symmetry factor, but also the design rules, manipulation accuracy, the
stability of structural units, and thermodynamic control should be considered for
spatial and hierarchical arrangement in protein assembly processes. Naturally
oligomeric proteins always exhibit finite point group symmetries. These unique
structural features combined with specific design rules provide a higher-order
control for assembly design to develop a series of polyhedral structures. Arai et
al. have recently discovered that the application of “nanohedra” design rule to
two oligomeric protein domains may result in four distinctive nanostructures by
creating a fusion protein via a relatively rigid peptide linker (61). Highly stable
symmetric oligomers, dimeric rod-like WA20 protein and trimeric β-propeller-like
foldon domain, were selected as the stable framework and 3-arm branched
junction, respectively. Meanwhile, two- and three-fold symmetry constraints
were imposed in the design of WA20-foldon fusion protein for self-assembly
into barrel-like, tetrahedron-like, triangular prism-like, and cube-like structures
(Figure 6a), the former two of which have been determined by small-angle
X-ray scattering (SAXS) analysis. By careful manipulation of the symmetry
axes of two different oligomeric proteins using genetic fusion method, a cubic
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protein cage with the largest size reported so far (an outer diameter of 225
Å and an inner diameter of 132 Å) was generated on the basis of trimeric
2-keto-3-deoxy-6-phosphogalactonate (KDPGal) aldolase and dimeric N-terminal
domain of FkpA protein (Figure 6b) (62). Native mass spectrometry (MS) data
further revealed that the conformational flexibility of protein building blocks
may affect the self-assembly process, leading to two additional self-assembling
architectures, 12-subunit tetrahedron and 18-subunit triangular prism. These
hollow porous nanostructures can be extensively studied for macromolecule
encapsulation, assisted crystallization, and X-ray analysis.
Accurate manipulation of protein interfaces allows greater structural
complexity for protein assemblies. Computational methods contribute to atomic
level understanding of the binding specificity between individual protein subunits,
which can assist protein engineering by de novo designing high affinity interfaces
and finding suitable binding geometries in the construction of higher-order
protein assemblies. The prediction of “hot spot” residues for amino acid
sequence design were demonstrated to be most effective in the creation of an
energetically favorable interface for driving the self-assembly of proteins into
cage-like protein nanostructures. Recently, Baker and co-workers reported
two remarkable examples of computational design guided protein assembly to
mimic virus capsid structures. RosettaDesign calculations was performed to find
low-energy, symmetric PPIs for precise definition of the relative orientations
of protein building blocks. In order to construct tetrahedral (T) and octahedral
(O) cages, a C3-symmetric protein trimer with 3-fold rotational symmetry axis
was chosen as the building block, a set of which tightly associated with each
other along the 3-fold axes of the target architectures to achieve the desired point
group symmetries (63). Using a similar strategy, heteromeric self-assembly of
two distinct protein trimers or a protein trimer and a protein dimer into either
T33 or T32 symmetric cage can be realized by alignment of the 3-fold or 2-fold
axis of each building block with the corresponding axes of dual tetrahedral
architecture (Figure 6c) (64). Looking forward, developing new theoretical tools
and algorithms to guide experimental design could greatly expand the diversity of
biomimetic nano/microstructures beyond nature’s materials.
Other factors that complicate 3D self-assembly design were also evaluated.
It is noteworthy that large arrays failed to assemble due to the inherent flexibility
of building blocks. The design of more rigid self-assembling components that
contain multi-arm junction motifs offers both stable framework and increased
valence for assembly of complex, multi-dimensional architectures. Mao et al.
synthesized three different types of DNA strands to assemble into symmetric
polyhedron for immobilization of proteins onto its surface (65). The long DNA
strands (L) coupled with medium strands (M) and short peripheral strands (S)
successfully created DNA duplexes with sufficient stability and rigidity in the
formation of polyhedral edges and joints. Introduction of a biotin moiety into
strand S constituted several trivalent sites for multi-site protein display with
strong binding affinity and freedom control. The engineered protein/DNA binary
material showed the virus-like structure that may find application in the design
of vaccines to elicit immunity against viruses. Furthermore, the dimensionality
of protein assemblies was proposed to be affected by thermodynamic/kinetic
Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1
ACS Symposium Series; American Chemical Society: Washington, DC, 2017.
control. In general, 2D and 3D structures were under thermodynamic control
while the structures of lower dimension were under kinetic control. Tezcan et
al. demonstrated that Zn2+-mediated crystalline protein arrays were irreversibly
regulated by external stimuli, in which 1D protein nanotubes as an intermediate
was formed by kinetically fast nucleation and can be progressively converted into
thermodynamically stable 2D and 3D planar arrays under low metal concentration
and pH (Figure 6d) (66). This feature makes supramolecular coordination protein
assemblies a versatile platform to engineer functional biomaterials under highly
controllable conditions.
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Conclusions and Future Prospects
Molecular-level control of protein self-assembly into 1D, 2D, and
3D nano/microstructures represents an important step toward developing
protein-based functional materials. Although current research is still far from
reproducing the functionality of natural systems, significant progress has been
made in the rapidly growing field during the past couple of decades. First,
several strategies, including biotechnological strategies, chemical strategies, and
their combinations, have been established to dictate protein self-assembly into
highly ordered architectures, which provide the engineering foundation for the
pursuit of versatile functionalities on an artificially created platform. Secondly,
de novo design of new interaction surfaces to drive protein-protein association
increases the level of controlled complexity and hierarchy, leading to the growth
of structural diversity in fabricating more sophisticated protein architectures.
Thirdly, the underlying mechanism that governs the sizes, shapes, and properties
of protein assemblies are beginning to be explored. Understanding the key
factors involved in the formation of specific self-assembling morphologies may
facilitate the future design of novel protein assemblies in a predictable way.
The next stage will need to place more emphasis on application development.
Custom-designed protein materials is concerned with both the structural design
and selective functionalization on periodic protein arrays to achieve precisely
addressed functionalities. The recent successes in some self-assembling protein
systems indicate a great potential for improving the performance of functional
materials, ranging from biocatalysis, biodetection, vaccine design to targeted and
controlled drug delivery. The remarkable growth in this field will continue to
be fueled by the development of interdisciplinary collaborative efforts between
nanoscience, materials science, and chemical biology, which are expected to
bring new breakthroughs in engineering bioinspired materials.
We acknowledge the financial support from the National Natural Science
Foundation of China (nos. 21234004, 21420102007, 21574056, 91527302,
21474038, and 21004028), the Chang Jiang Scholars Program of China, and
the Science Development Program of Jilin Province (nos. 20140101047JC and
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