Developing Biopolymer Mesocrystals by Crystallization of Secondary

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Developing Biopolymer Mesocrystals by Crystallization of Secondary Structures Fei Tao, Qian Han, and Peng Yang Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b03300 • Publication Date (Web): 15 Dec 2018 Downloaded from http://pubs.acs.org on December 20, 2018

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Langmuir

Developing Biopolymer Mesocrystals Crystallization of Secondary Structures Fei Tao1, Qian Han1, Peng Yang1,

by

*

1. Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710119, China. Correspondence and requests for materials should be addressed to P.Y. (email: [email protected]) KEYWORDS:

Mesocrystal,

Nucleation,

Crystallization,

Secondary Structure, Amyloid

Abstract: Particle-based mesocrystals have been developed for over 10 years, however, examples of biopolymer mesocrystals are rather scarce. The synthesis of particle precursors of biopolymers,

the

crystallization

identification

process

and

thus

of the

particle-mediated mesocrystals

of

biopolymers are challenging. Here, we summarize the existing examples of biopolymer crystallization based on self-assembly of the secondary structures, which could induce the formation of biopolymer mesocrystals. Simple secondary structures such 1

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as β-sheet or α-helix, as basic building units could provide a useful tool to design biopolymer mesocrystals.

Introduction The single-crystalline materials with high modulus and hardness could display the outstanding performance in energy harvesting, conduction, conversion and storage1 ， but the single-crystals formed by single atoms, ions or molecules along classical crystallization pathway could not be able to meet the requirements in exquisite controlling structures and morphology2-3.

Mesocrystals

from

the

particles-mediated

nonclassical crystallization pathway have attracted most attentions

due

to

controlled

morphology

by

using

self-assembled organic superstructures, inorganic or organic additives, and templates with complex functionalization2. Collagen molecule and related mimetic polypeptides could assemble into triplex nanofibers4, amelogenins or related fragments

could

aggregate

and

grow

into

ribbon-like

nanostructures5, 6. It has been proved that both self-assembled superstructures could direct the crystallographic alignment of hydroxyapatite crystals in [001] direction5, 7. Except for 2


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organic matrix, the inorganic matter magniesium could be also discovered

in

most

biogenic

calcified

minerals8.

In

mesocrystallizaiton pathway of calcium carbonate, magniesium could facilitate the formation of Mg-containing amorphous calcium carbonate precursor, which could transform into calcite mesocrystals9. Amorphous precursors or nanocrystals could

be

crystalized

and

aligned

into

mesocrystalline

structures with assistance of 1D-, 2D-, 3D- or self-templates, which could bond the nanoparticles by non-covalent bonding interactions and then direct the mesoscale assembly of nanoparticle through steric confinement of templates to programmatically control the complex and desirable mesoscale to macroscale mesocrystalline structures.10 The term mesocrystals have been proposed about 10 year ago11, since then, a variety of examples of mesocrystals in both biominerals and synthetic materials have been identified, which rapidly gain more and more interests in material science12-14. Mesocrystal proposed by Cölfen and collaborators is exactly defined as “a nanostructured material with a defined long-range order on atomic scale, which can be inferred from the existence of a wide-angle diffraction pattern together

3


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with clear evidence that the materials consist of individual nanoparticle building units”11-14. For

a

colloidal

system,

monodispersed

inorganic

nanocrystals with directional physical properties are aligned in mesocrystals through direction of electric15-16, magnetic fields17-18 or intrinsic dipole force18-20 for assembly of nanocrystals.

This

type

of

mesocrystal

consisting

of

nanocrystal arrays with both orientation and position order has the potential to couple and amplify the properties of the anisotropic nanocrystalline building blocks. For example, the magnetite mesocrystals consisting of 6-10 nm nanoparticles have superparamagnetism and high magnetization, which were different from individual nanoparticles within 30 nm that could not be magnetized by external magnetic field due to their low magnetization18. The organic-inorganic hybrid mesocrystal system could be easily

discovered

materials21-22.

in

Mineralized

biominerals tissues

and

produced

biomimetic by

living

organisms perfectly incorporated abundant nanoparticles into suprastructures by selective attachment or templating of organic molecular additives23-26. The soft and ductile organic 4


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layers in-between hard and stiff mineral nanoparticles could effectively hinder crack propagation to yield crystalline materials with high mechanical performance26-27. For instance, nacreous-type minerals in mollusk shell were lightweight multilayered composites, and consisted of mesocrystalline domains

with

a

high

strength

and

remarkable

fracture

toughness, which was 3000 times higher than pure minerals26. Similarly, sea urchin spines consisting of amorphous phase and

crystalline

CaCO3

were

optimized

in

mechanical

properties28. Most biominerals exhibit impressive performance and multifunctional properties due to exquisite structural control from nanoscale to mesoscope, or even to macroscope2-3, 11.

The

structure

control

and

design

principles

in

biomineralization revealed by Addadi, Weiner and Mann26, inspired many strategies to develop biomimetic analogues of several natural biominerals, such as, mesocrystalline calcite spicules29 and artificial nacre30-32, which were formed with the aid of synthetic or natural polymers.

5


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Figure 1. A) Scanning Electron Microscopy (SEM) image of alanine

mesocrystals

generated

from

saturated

alanine

solution in presence of 1 wt% of PEG4700-PEI1200-S-iBAc after cooling from 65 to 20℃, B) the proposed model of DL-alanine mesocrystals based on along [100] directional oriented attachment

of

DL-alanine

crystalline

nano-platelets

in

presence of PEG4700-PEI1200-S-iBAc. Figures are reproduced from ref. 27 with permission of Wiley-VCH. Although

many

architectures

examples

have

(such

proven

as

that

the

hybrid

organic-inorganic,

amorphous-crystalline) of mesocrystals have obviously huge advantage to the single phase materials, for an integration of nano-units and bulk structural properties, the definition and application of organic mesocrystals are highly limited in some small amino acids and organic molecules33-34. Alanine and lysine were earliest examples to form organic small 6


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molecular

mesocrystals35-37.

The

morphology

control

of

DL-alanine mesocrystals could be easily realized by addition of

poly(ethylene

glycol)-block-poly(ethylene

imine)-S-isobutyric acid (PEG4700-PEI1200-S-iBAc) (Figure 1A), which

could

induce

oriented

alignments

and

fusion

of

DL-alanine nano-platelets (Figure 1B)35. Alternatively, like the biominerals, lysine mosaic mesocrystalline thin film showed the tunable hierarchical structures by the addition of poly(acrylic acid) (PAA) (Figure 2)36-37, which could induce the

formation

of

liquid

precursors.

Remarkably,

each

polydomain consisting of nanoparticles (Figure 2B-D) was mesocrystalline,

but

polycrystalline.

The

the

whole

lysine

thin

double-hydrophilic

block

film

was

copolymer

PEG-block-PEI could also mediate the perylene derivative to form ultralong organic mesocrystals with outstanding optical and electronic properties38, which showed the potential in organic electronics and optoelectronic applications.

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Figure 2. A) The formation of lysine mesocrystalline thin film under polarized optical microscope, lysine liquid precursors first crystallized into spherulitic thin film induced by PAA during

solvent

transformation

evaporation resulted

and

in

subsequently

the

formation

structural of

lysine

polycrystalline thin film containing mesocrystalline domains, B-D) AFM images at three different length scales, displaying hierarchical

mosaic

structures,

which

consisted

of

nanoparticles. Figures are reproduced from ref. 36 with permission of Wiley-VCH. In contrast to inorganic and small molecular organic mesocrystals, the examples of macromolecular mesocrystals are quite rare since (bio)organic macromolecules usually present a poor crystallization ability from their solvate states2, 11-13.

Considering the conformational transformation of chains 8


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via

unfolding

or

folding,

formation

mechanism

of

biomacromolecular mesocrystallization is much more complex than inorganic or small organic molecules. In the case of proteins (the main scope of this feature article), the formation of simply assembled (or self-folded) secondary structures (such as amyloid structures) from different amino acid

residues

may

drive

a

new

biomacromolecular

crystallization pathway toward biopolymer mesocrystals39 (Figure 3). In contrast to inorganic mesocrystals, the building blocks of such biomacromolecular mesocrystals might be the secondary structural assemblies between protein chains (dense amorphous or crystalline states), which are formed through folding/unfolding and reorganization of protein chains via hydrogen bonding, hydrophobic interaction and/or spatial

conformational

matching.

In

this

process,

the

thermodynamic/kinetic may thus promote the oriented assembly and

crystallization

of

ordered

mesocrystalline structures.39

9


nano-units

into

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Figure 3. The conceptual evolution from inorganic to macromolecular mesocrystals: A) The crystallization pathway based on inorganic mesocrystals; B) the formation and self-assembly of protein nanocrystals to form (bio)macromolecular mesocrystals. Figures are reproduced from ref. 39 with permission of Wiley-VCH. For biopolymer, nonclassical multistage assembly could generate

crystals

but

also

fibrillar

structures.

The

condensed liquid precursor are ubiquitous and significant intermediate phase for production of the ordered structural nucleus, which could directly grow into fibers or crystals. The most protein assembly may not necessarily need to pass through the atypical intermediate phase, mesocrystals that could be only discovered in particle-based nonclassical crystallization process. In biopolymer crystallization, the driving force may be weak for ordered phase transition from free energy trap resulting in formation of stable amorphous 10


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states40-41.

Therefore,

we

start

our

discussion

about

non-classical two-step nucleation of biopolymer crystals, which highlights the importance of phase transformation in sequential

processes

involving

formation

of

amorphous

precursors, relaxation of intermediates containing events of folding and conformational transformation, and crystalline transition42-43. The selected examples will introduce how the macromolecular or biopolymer nano-structures assemble into mesocrystals, moreover, the related noncrystalline ordered assembly

(amyloid

fibrillation)

of

biopolymer

is

also

discussed. Although most of existing studies could not provide well-defined evidences to confirm the formation of biopolymer mesocrystals with the lack of for example evidences for critical 3D orientation, we would still discuss some selected work on the assembly regulation of proteins, which may inspire us to develop flexible supramolecular chemistries towards the design of more and more biopolymer mesocrystals. It is also beneficial to summarize the existing knowledge about macromolecular mesocrystals and their formation mechanisms to explore their applications in biomedicine, bio-catalysis and surface engineering.

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2. Nucleation through assembly of molecular secondary structures In recent decades, the studies on protein crystallization proposed that ordered nucleus was formed through complex two-step

process44-45,

rather

than

monomer-to-monomer

addition. Such nonclassical two-step nucleation pathway typically included the formation of condensed precursor via molecules and ions aggregation and then subsequent phase transformation into new ordered phase through structural fluctuation44. fluctuation

The

was

nucleation

prior

to

pathway

structural

in

which

density

fluctuation

could

effectively reduce the kinetic energy barrier to formation of ordered phase44-49. Particularly, protein aggregation via protein unfolding or misfolding could produce a highly ordered amyloid state. In such pathway, the β-sheet assemblies as initial short-range ordered nano-units, could further pack into long-range ordered noncrystalline amyloid fibrils, which were associated with human disorders50. In the energy landscape of protein folding and aggregation, a cragged route from native state to amyloid state exhibited the multiple ‘funnels’, which represented

a

transformations

series of

of

biopolymers

complex involving

12


conformational formation

of

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intermediates such as partially folded states, amorphous aggregates

and

oligomers

(Figure

4A)41,

50

before

final

formation of highly ordered amyloid states. When the free energy was inadequate to overcome the conformational energy barriers of chains, the intermediates could be last for long life-time.

Moreover,

amyloid

crystals

as

the

most

thermodynamic stable amyloid states had no mesoscopic chiral structural twisting51, which could be depressed through highly demanding kinetic controlling during nucleation process (Figure 4B).

Figure 4. A) Energy landscape scheme of protein folding and aggregation and B) energy landscape for the main amyloid polymorphs including twisted ribbons, nanotubes and crystals proposed by J. Adamcik and R. Mezzenga. Figures are reproduced from ref. 50 and ref. 51 with permission of American

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Association for the Advancement of Science and Wiley-VCH respectively. The nucleation of macromolecular crystals is more complex process than inorganic or small organic molecular crystals since various factors could trigger aggregation and following crystallization

of

soluble

biopolymers.

Proteins

could

crystallize in vivo under some stimulates from metal ions, hydrolase, genetic mutation and virus52. For instance, free insulin in cells could assemble into hexamers and crystallize rapidly when the concentration of zinc ions increased53. Peroxisomes involving a variety of chemical processes in eukaryotic cells, could aggregate and crystallize into protein crystals with regular shape by the hydrolysis action of catalase, urea oxidase and alcohol oxidase54. Glutamic residues in hemoglobin were mutated to lysine residues and induced crystallization of hemoglobin C in the red blood cells, which resulted in hemoglobin C disease55. In addition, heterogeneous nucleation of proteins exist in vivo, for example, when virus invaded into cells, a large amount of protein

particles

including

spheroidin,

polyhedron

and

granule, could form crystalline shell to encapsulate virus template to facilitate the invasion56. 14


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At initial stage of crystallization, rapid nucleation could restrict the direct growth of nanocrystals but also promote the formation of mesocrystal intermediates by oriented assembly of nanocrystals. However, ordered phases arising from amorphous aggregates require relaxation process that have limited nucleation of macromolecular crystals57-58. For instance, Chung et al58 used in situ atomic force microscopy (AFM)

to

investigate

multistage

S-layer

protein

crystallization pathway including condensation of protein, relaxation from condense phase to ordered nucleus and growth of 2D crystals (Figure 5). Crystallization of S-layer protein on bilayer lipid was not the mesocrystallization process, but a typical example to explain that high energy barrier of nucleation

could

inhibit

the

formation

of

biopolymer

mesocrystals. The ordered tetramers were easier formed at edge of 2D protein crystals rather than self-nucleation, due to ordered and lower energy interface supported by formed 2D protein nanocrystals. Nucleation of S-layer protein was limited by high energy barrier, due to the complex molecular conformational change to form stable crystalline assemblies from isolated states. Once few nucleus formed, the interface of ordered phase could provide a low energy pathway for 15


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molecular folding/unfolding and assembly, which could depress the subsequent nucleation of tetramers and assembly of nanocrystals but promote the direct growth of nanocrystals. In other words, like inorganic mesocrystallization, abundant and rapid formation of nanocrystals by lowering energy barrier at initial stage of crystallization is prerequisite for following

oriented

assembly

of

nanocrystals

to

form

biopolymer mesocrystals.

Figure 5. 2D crystallization model of S-layer protein on supported lipid bilayers. Adsorbed proteins aggregated to form condensed phase. After long-time relaxation process, ordered nucleus consisting of tetramers rise from amorphous aggregate, 2D crystal growth could be then achieved through the addition of tetramers (formed by self-catalyzed process) at boundary of 2D crystal so that crystalline nucleus could 16


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lower the free energy barriers to formation of tetramers. Figure is adopted from ref. 58 with permission of Proc. Natl. Acad. Sci. U. S. A. The high-ordered structural multimer as building blocks in biopolymer crystals formed through complex process including multiple molecular unfolding, folding and assembly, which could prolong the relaxation and limit the nucleation. Furthermore, if the structural fluctuation is too weak to give rise to an ordered phase transition, a metastable condensed phase will last for a long life-time44. Such limited nucleation of ordered phase could be discovered in amyloid fibrillation process59, which was associated with human disorders60. The amyloid fibrillation process produced a ‘S’ type kinetic curve as measured by Thioflavin T (ThT) fluorescence, which showed three stages containing an initial long lag phase, followed by a rapid exponential growth and completed by a saturation phase. The long lag phase stage represented the long-time process for the formation of ordered structural units, which involved in protein unfolding, misfolding, aggregation by exposed hydrophobic area and transition into β-sheet-rich structure.

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Simplification of building blocks from complex high-order structures to basic secondary (such as β-sheets or α-helix), could be a good strategy to shorten phase relaxation process and promote nucleation and crystallization of biopolymer crystals. In such pathway, formation and assembly of secondary structures has low demand in allosteric regulation, besides, the

biopolymers

with

longer

chains

have

advantages

in

crystallization because they could provide more exposed activity

sites

for

formation

or

assembly

of

secondary

structural units. For example, Zuckermann et al61-62 revealed that the crystallization of peptoids based on Σ-sheets as building blocks followed this principle, and Σ-strands allowed the backbone conformation to keep simple linear and untwisted structure, and the peptoids with longer chains were more easily to form crystalline bilayer sheets. However, in contrast to peptoids they used, most of proteins with long chains in nature generally are globular structures with complex three dimensional configurations, which are maintained by intramolecular folding and embedding the binding sites into hydrophobic cores. The key to the native protein crystallization pathway through ordered packing of secondary structural units is how to release the binding sites 18


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to inter-molecular secondary structure from original locked conformation of spherical molecules. It has been reported that the intramolecular disulfide bond is critical to stabilize protein tertiary or quaternary structures63-64. As a result, the reduction of disulfide bond of proteins led to a mild unfolding of proteins65, which subsequently induced the transformation of chain secondary structures into predominant β-sheets in insulin single crystals66. In this regard, Yang et

al

developed

a

strategy

to

realize

the

nucleation-crystallization of proteins by unfolding native lysozyme,31

insulin,

bovine

serum

albumin

(BSA)

or

α-lactalbumin via the reduction of their intramolecular disulfide bonds67-83. Tris(2-carboxyethyl)phosphine (TCEP) reduced disulfide bonds effectively in lysozyme39, 67-69, which consequently

induced

protein

unfolding

and

then

self-assembled unfolded protein chains into short-range β-sheets without complex pre-steps (Figure 6A). The reduction of disulfide

bonds

was

clearly

reflected

through

Raman

spectra

and

N-(1-pyrenyl)maleimide (NPM) assay (Figure 6B), and β-sheets transformation was then characterized by Circular Dichroism (CD) and Fourier Transform infrared (FTIR) spectra (Figure 6C). The growth of β-sheets by intermolecular hydrogen bonds and assembly of β-sheets by hydrophobic interactions were further evaluated 19


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by ThT and 1-anilino-8-naphthalene sulfonic acid (ANS) assays (Figure 6D). Finally, the structures of such short-range ordered β-sheet assemblies from unfolded proteins was clearly revealed by Freeze-etching Transmission Electron Microscopy (TEM) (Figure 6E).

Figure 6. A) A schematic of nucleation pathway for unfolded protein

crystals

through

inter-chain

self-assembly

of

short-range β-sheets; B) Raman spectra and NPM staining for reduction of disulfide bonds in lysozyme; C) CD and FTIR spectra for formation of short-range β-sheets from unfolded protein; D) ThT and ANS assays for growth and assembly of β-sheets;

E)

Freeze-etching

TEM

image

20


of

short-range

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alignments transform

of

β-sheets

(FFT)

and

(inset);

F)

corresponding TEM

and

fast

HR-TEM

Fourier

image

of

‘core-shell’ structural biopolymer nanocrystals; G) a cartoon for crystallization of short-range β-sheets supported by corresponding SAED, XRD and solution SAXS results. Figures are adopted from ref. 39 with permission from Wiley-VCH. The unfolded protein aggregates containing short-range inter-chains alignments were sensitive to solvent environment so that structures of such short-range β-sheets assemblies could be tuned at different conditions39,

67-83.

Under quasi-equilibrium condition, short-range β-sheets

could be further crystallized to form vast protein nanocrystals39 (Figure 6F). These nanocrystals had typical ‘core-shell’ structure that crystalline cores orderly packed from β-sheets were embedded into amorphous flexible chain shells, which were similar to the

structure

biomineralization

of

organic-inorganic

and

could

orientedly

nanocrystal assemble

in into

mesocrystals (vide infra). The crystalline ‘core’ from staggered packing of short-range β-sheets were then supported by Selected Area Electron Diffraction (SAED), X-ray diffraction (XRD) and solution Small-Angle X-ray Scattering (SAXS) measurements (Figure 6G). Notably, the β-sheets are long-range ordered arranged with mesoscopic chiral helix structures in classical amyloid assembly, however, in Yang’s system, 21


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β-sheet aggregates assembled from unfolded protein chains were short-ranged, and underwent flat-like packing to be crystallized. This protein unfolding system actually made use of a mild protein conformation transition to be near the quasi-equilibrium state. In contrast to the nucleation at quasi-equilibrium condition, a rapid non-equilibrium assembly of short-range β-sheet aggregates (superfast amyloid-like protein assembly) could produce the 2D protein nanofilm

at

air/water

interface

and

sub-micron

scale

particles in bulk solution at same time69-72. As a photoresist, the 2D protein nanofilm could support a facile and green photolithography strategy, which could obtain the tunable patterns through short-time UV/e-beam exposing under covered mask and removing photoresist with water70,

72.

Like amyloid

structures in nature, the protein nanofilm has adhesion capability to different material surfaces due to multiplex binding (including hydrogen bond, hydrophobic interaction, electrostatic interaction, metal-S interaction and surface roughness) and antibacterial property due to positively charged

and

hydrophobic

residues

exposed

on

the

film

surface73-76. Furthermore, the protein nanofilm could be an ideal intermediate-layer material for guiding electroless 22


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deposition,

hydroxyapatite

mineralization

and

chemical

modification on inorganic, organic and even living cell surface70,

77-79.

On the other hand, the sub-micron particles

aggregate into network structures, which could provide a platform

with

emerging

superhydrophobic

applications

surface

for

including

facilitating

a

protein

crystallization, a smart surface for capturing or releasing drug loaded cell-sized lipid vesicles and a biochip for detecting small molecules and macromolecules80-83. 3. Mesocrystallization based on assembly of secondary structural nano-units Nanostructural units based on ordered packing of basic unitary secondary structures (such as helix or sheets) of biopolymers, like inorganic nanocrystals with anisotropy, could assemble into mesoscale ordered suprastructures by selective attachments. The pathway of such mesoscale assembly may

be

different

between

helical

and

β-sheet-based

biopolymers. Helix from self-folding of biopolymers has intrinsic

dipole

fields

due

to

unsymmetrical

helical

molecular conformation. In such intrinsic dipole fields, helical

biopolymers

are

easily

packed

into

structured

nano-units with high aspect ratio such as platelets, rods and 23


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fibers84, which could further assemble into mesoscale or even macroscopic alignments via addition of external physical fields. In contrast, the β-sheets packing between unfolded or misfolded biopolymers could produce highly ordered amyloid aggregates. The amyloid crystals without chiral twisting or helix

displayed

the

alignments

of

protofibrils

at

nano-mesoscale, however, acquisition of amyloid crystals based on classical nucleation and crystallization were quite difficult and highly restricted in short amyloid peptides. 3.1 The alignment of helix-based nano-units by external physical fields The helix structure is the most common secondary structure of

protein,

which

could

be

also

gained

by

synthetic

supramolecular polymer. A series of designed peptides, containing a minimum of three repeats of the ACHC-ACHC-b3-hLys triad85-87, folded into stable helical conformations resulting from segregation of the hydrophobic cyclohexyl ring and hydrophilic b3-hLys residues87. Such polypeptides had very stable helix conformational structures, which exhibited a good crystalline ability. The morphology and orientation of crystals could be tuned by adding the nonionic surfactant P123 ((ethylene

glycol)20-(propylene 24


glycol)70-(ethylene

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glycol)20) to 1D rod, 2D sheet or complex 3D structure such as

windmill-shaped

and

tooth-shaped

morphologies87-91.

Importantly, Lee et al92 proved that the rod-like architecture of β-peptide foldamers could be aligned under external static magnetic fields due to amplification of the anisotropic diamagnetic

susceptibilities

well-ordered

packing

and

originating

crystalline

from

properties

the of

self-assembled oligomers (Figure 7A, B). The external static magnetic fields could induce alignment of helix foldamers (Figure 7C-E). It was possible to further orient the helix foldamer-based microrods in real time using a dynamic magnetic field

and

this

supramolecular

property machines

was

manipulated

capable

of

to

construct

translating

dynamic

magnetic field into instantaneous motions at microscopic and macroscopic scales. In nature, collagens as triple helical biopolymer are the basic structural building blocks of extracellular matrix. Diversity of assembly of collagen mimetic peptides, gels and crystals could be mediated through sequence engineering93-94. Ruberti95 reported that a collagen fiber was drawn from a droplet surface, at which collagen was concentrated after water evaporation process (Figure 8A). In collagen fiber 25


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Page 26 of 48

drawing process, extensional mechanical tension drawing outward to air/water interface could induce alignments of collagen

nanofibrils

outside

of

fiber

(Figure

8B-D),

alternatively, the tension flow was weak in core area resulting in disorganization of collagen fibrils (Figure 8B). These results provided a pathway to scalable connective tissue manufacturing and supported a mechano-biological model of collagen fibril deposition and growth in vivo.

Figure 7. Crystal packing models of A) rhombic rod foldecture (BocNH-ACPC6-OH)

and

B)

rectangular

plate

foldecture

(BocNH-ACPC8-OBn), black arrows representing the magnetic responding direction of the foldectures under external static the magnetic field, C) a cartoon to illustrate the alignment of foldectures during solution evaporation under vertical and parallel

directional

static

magnetic;

26


SEM

results

for

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Langmuir

alignments of D) rhombic rod and E) rectangular plate, scale bar are 5 μm. Figures are adopted from ref. 92 with permission of Nature Publishing Group.

Figure 8. A) A schematic of fiber drawing process, in which first collagen was condensed at air/water interface during water evaporation, and an enriched surface was formed after 150 s with dry nitrogen gas flowing. A collagen fiber could be reliably drawn from the enriched surface using a glass microneedle to pierce the droplet surface and draw back outward; B) TEM image for longitudinal section of collagen fiber consisting of highly ordered organized fibrils within crystalline ‘shell’ and disordered ‘core’; C) TEM image for alignments

of

collagen

fibrils

in

‘shell’,

and

D)

high-magnified TEM for rectangular region in crystalline ‘shell’. Figures are adopted from ref. 95 with permission of American Chemistry Society. 27


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Page 28 of 48

It was emphasized that above examples were not typical biopolymer mesocrystals, however, the oriented alignments of biopolymer nano-units driven by

external

physical

field

was

similar

to

the

mesocrystallization of inorganic colloidal nanocrystals. Accordingly, we may predict that helical structure-based biopolymer mesocrystals may be possibly generated through such external field-driven assembly pathway in future study. However, the question is: although the assembly in these examples (e.g., Figure 7, 8) might present certain in-plane orientation, however, the critical information of 3D crystallographic orientation were not clear for these examples. 3.2 β-sheet biopolymer mesocrystals The β-sheets comprise extended polypeptide β-strands that are linked laterally via hydrogen bonds. Usually β-sheets prefer to pack through hydrophobic face-to-face interactions with other β-sheets to form stable and compact layered sandwich-like structures96. β-sheet assembling often produces the chiral twisting structures, such as amyloid fibrils associated with neurodegenerative diseases, due to intrinsic flexible fluctuations of β-sheets97 and accumulated elastic distortions from rigid units incorporation98. However, the polymorphous of amyloids suggested existing of flat-like 28


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amyloid crystals without chiral structures (Figure 4B). In some situations, amyloid flat ribbon-like crystals could be obtained through lateral assembly of amyloid protofilaments, which could balance the helix from the ribbon bending. For instance, the self-assembly of the 26-residues peptide fragment from the R3 domain of Tau protein, could produce giant ribbon-like amyloid crystals generated from the lateral assembly of up to 45 individual protofilaments, corresponding to a record-high width of up to 350 nm (Figure 9)99. In such process, the β-sheets were highly ordered packed via hydrogen bonding along the long axis of ribbons, but the lateral ordered linking of β-sheets via hydrophobic interaction might be interrupted due to slightly twisting of protofibrils, which could

induce

the

mismatch

of

conformation

between

inter-fibrils in ribbons. In spite of few examples on amyloid crystals,

the

competitive

relationship

between

amyloid

fibrillation and crystallization was more favorable to the amyloid fibrillation for long-chain polypeptides, which could more easily induce the structural twisting that could not be neutralized during fibrillation process100. As a result, the amyloid

crystals

for

long-chain

proteins

accessible, due to entropic restrictions43. 29


become

less

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Figure 9. AFM height images (a, c) and corresponding AFM phase images (b, d) at different magnification for R3 peptide amyloid crystals. Figures are reproduced from ref. 99 with permission of Wiley-VCH. Based on existed examples of inorganic mesocrystals and mesoscale alignments from assembly of secondary structures, a potential three-staged model of β-sheet-based biopolymer mesocrystallization was proposed by Yang et al39. Similar to inorganic substances (Figure 3A), such biopolymer mesocrystallization pathway included two-step nucleation and crystallographic assembly of β-sheet-based nanocrystals (Figure 3B)39. In this process, the crystalline ‘core’ consisting of hierarchical multilayer of β-sheets was compact and rigid to against the structural fluctuations of β-sheets. Moreover, the unfolded chains with partial alignments as 30


Page 30 of 48

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remained outside of crystalline ‘core’ were flexible ‘shell’, which

could

release

crystallization

and

the

fusion

elastic

distortions

during

between

neighboring

protein

nanocrystals. After nucleation period indicated by the balance of ThT and ANS assay, such

‘rigid-soft’

heterostructure

could

depress

structural twisting and promote the ordered packing of flat-like

β-sheet

for

further

crystallization

through

assembly and fusion to form flexible multilayered protein mesocrystals (Figure 10A). For instance, the kinetic energy barrier from such amorphous ‘shell’ to limit the growth of nanocrystals at 37℃, could be then overcame at 47℃ to promote crystallographic assembly and fusion for formation of biopolymer mesocrystals (Figure 10B-D). The resultant protein mesocrystals

could

subsequently

transform

into

single

crystals via fusion of nanocrystals after longer incubation (Figure 10E-G). Further, the single crystal could grow and pack into multilayered mesocrystals (Figure 10H, I).

31


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Figure 10. A) A cartoon to show the mesoscale assembly of unfolded protein nanocrystals to form flexible multilayered mesocrystals and corresponding ThT and ANS staining assays; B-D) TEM, high-resolution TEM (HR-TEM) and corresponding SAED images for the particle-based mesocrystals; E-G) TEM, HR-TEM and corresponding SAED for single crystals as a fusion product of (B-D), H-I) TEM and HR-TEM images for flexible multilayered 32


Page 32 of 48

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Langmuir

protein mesocrystals. Figures are reproduced form ref. 39 with permission of Wiley-VCH. The

principle

of

macromolecular

mesocrystallization

delivered new tools and possibilities into the hands of chemists, providing great promise for the generation of flexible (bio)macromolecular crystalline structures in a much broader and potentially useful way. The significance of the proposed biopolymer mesocrystallization could be reflected in the following aspects: (1) as a product to mimic the crystallization of globular protein in vivo52, the biopolymer crystals from such mesocrystallization indicated a new insight for pathology of disorders induced by non-classical assembly of biopolymer under similarly mild conditions (as we known, normally, protein crystallization at low concentration and mild conditions is hardly achieved in vitro, which nonetheless is easily obtained in nature and successfully acquired in our system); (2) as highly ordered supramolecular assemblies, biopolymer mesocrystals could provide a new strategy to design and fabricate complex crystalline biopolymer materials through assembly of secondary structures, which is hardly realized before (in classical polymer crystallization, perfect polymer crystal is hardly achieved)101; (3) as a special class of biopolymer colloidal crystals, the principles of biopolymer mesocrystallization could enrich and direct new supramolecular assembly chemistry of protein colloids96, 102. 4. Conclusion and Outlook 33


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Page 34 of 48

In summary, the systematic research on mesocrystals started over 10 years ago, but the biopolymer mesocrystals are just in

babyhood.

synthesis

The

of

limited

particle

identification

analytical

precursors

particle-mediated

of

techniques

impede

biopolymers,

crystallization

the and

mesocrystals of biopolymers as well as characterization of their structures and properties. Moreover, macromolecular crystallization is a very complex process involving the chain folding or unfolding and conformational transition determined by thermodynamic/kinetic control. Helical biopolymers have the stable conformation and structures with well-defined sequences, and helix biopolymer-based nano-units could be aligned under external physical fields, which were the resemble

features

of

inorganic

colloidal

mesocrystallization. This may provide a workable strategy to synthetic helical biopolymer mesocrystals in future through fine regulating aligned nanocrystals or nanofibers into crystallographic orientations. On the other hand, β-sheet structures are highly unified at atomic level but could be formed with a broad range of sequences, which suggest that β-sheets based nano-units may possess higher assembly activity than helix-based nano-units 34


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Langmuir

due to easy formation of interchain β-sheets. On the basis of existing examples on inorganic mesocrystals and colloidal alignments, a biopolymer mesocrystallization pathway through hierarchically multistep assembly of secondary structures is finally put forward, which could increase the probability of nucleation of biopolymer crystals. Even only one successful example of unfolded protein mesocrystals from crystallization of inter-particles β-sheets has been identified via solid evidence, which could give an enlightenment that other β-sheets mesocrystals possibly existed in amyloid protein unfolding process. Therefore, crystallization of secondary structures presented constructive prospective on developing biopolymer mesocrystals. Generally,

mesocrystallization

nano-assemblies supramolecular

(e.g., assembly

crystallographic

includes

nanocrystals) of

these

orientations4,

nucleation and

followed

nano-assemblies 95.

The

of

with

universal

applicability of the method proposed in this article thus is based on the following two aspects: (1) as the basic structural unit, secondary structures such as α-helix or β-sheets were easily formed and obtained from self-assembly of predictable sequence, which were quite normal in literatures. This could 35


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Page 36 of 48

provide a solid basement to design and synthesize versatile biopolymer precursors for mesocrystals; (2) crystallization of secondary structures as an essential condition to form biopolymer mesocrystals is quite different to the normal crystallization of protein, which were usually reduced as spherical particles. Nano-phase assembled from β-sheets or

α-helix conformational chains exhibit structural anisotropy, which could direct selective attachment of nano-assemblies to form meso-structures or even mesocrystalline structures. Besides, there are many successful studies on control and regulation of supramolecular chemistry and assembly of a wide range of particles and colloids, it is thus expected to achieve easily

universal

applicability

of

biopolymer

mesocrystallization through regulation of supramolecular interactions

between

secondary

structures

or

their

aggregates94. As a outlook, biopolymer mesocrystals may have great potentials in related fields and can inspire the research of biomacromolecular mesocrystal, for instance: 1. Previous research proved that unfolded lysozyme could crystallize by mesocrystalline pathway. With this respect, 36


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Langmuir

more investigations may focus on whether other similar amyloid globular proteins can form mesocrystals after molecular chain unfolding. 2. As amphiphilic molecules, the phase transition behavior and assembly of nanocrystals for unfolded proteins in bulk may be completely different from that at a two-phase interface. 3. Crystallization mechanism based on unfolded proteins needs more investigations through sequence engineering. 4.

The

soft

materials

mesocrystallization

may

constructed

be

from

sensitive

to

the

biopolymer change

of

environments factors such as pH, humidity, metal ions and temperature, which could mediate biopolymer mesocrystals to exhibit dynamic properties. 5.

Inspired

by

silk

protein,

novel

β-sheet

mesocystal

assemblies based on unfolded proteins may offer opportunities to

fabricate

nanostructured

materials

mechanical properties. AUTHOR INFORMATION Corresponding Author

37


with

outstanding

Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

* Correspondence

and

requests

Page 38 of 48

for

materials

should

be

addressed to P.Y. (email: [email protected])

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT P.Y. thanks the funding from the National Natural Science Foundation of China (no. 51673112, 21875132), the 111 Project (no. B14041), the Fundamental Research Funds for the Central Universities (GK201801003, 2017CBY004) and Open Project of the State Key Laboratory of Supramolecular Structure and Materials (No. sklssm201827). Reference (1) Zhang, P.; Tachikawa, T.; Fujitsuka, M. et al. The Development of Functional Mesocrystals for Energy Harvesting, Storage, and Conversion. Chem. Eur. J. 2018, 24, 6295-6307. (2) Cölfen, H.; Antonietti, M. Mesocrystals and Nonclassical Crystallization, John Wiley & Sons, Chichester, 2008. (3) Bergström, L.; Cölfen, H. et al. Mesocrystals in Biominerals and Colloidal Arrays. Acc. Chem. Res. 2015, 48, 1391-402. (4) Engel, J.; Bächinger, H. P. Structure, Stability and Folding of the Collagen Triple Helix. 38


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For Table of Contents Use Only：

Secondary structures

Biopolymer Nano-units

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Meso-structures or mesocrystals

Developing Biopolymer Mesocrystals by Crystallization of Secondary

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