A capstone course for BioSUCCEED:

Biomass Fundamentals Modules 16, 17: Higher Order Functionality in Biomass: Self-Assembly
A capstone course for BioSUCCEED: Bioproducts Sustainability: a University Cooperative Center of Excellence in EDucation The USDA Higher Education Challenge Grants program gratefully acknowledged for support

This course would not be possible without support from:
USDA Higher Education Challenge (HEC) Grants Program

Article of Interest “Nanotube Formation from Renewable Resources via Coiled Nanofibers” – G. John et al., Advanced Materials 2001, 13, 715. Use of cardanol – synthesis of aryl glycolipids and self-assembly π-π stacking interactions assist self-assembly

Definition The spontaneous organization of individual components into an ordered structure without human/supernatural intervention. Self-assembly is the fundamental principle which generates structural organization on all scales from molecules to galaxies. It is defined as reversible processes in which pre-existing parts or disordered components of a preexisting system form structures of patterns. From Wikipedia, the free encyclopedia The concept of self-assembly is used increasingly in many disciplines, with a different flavor and emphasis in each. From the definitions, we can know the important features of self assembly are: spontaneous, that is, without the human’s intervention. The second feature is from disorder to order, from simple to complex. The third feature is that the procedure is reversible.

Types of Self-Assembly
Two main kinds of self assembly Static self-assembly (S) involves systems that are at global or local equilibrium and do not dissipate energy. For example, molecular crystals are formed by static self-assembly; so are most folded, globular proteins. In static self-assembly, formation of the ordered structure may require energy (for example in the form of stirring), but once it is formed, it is stable. Dynamic self-assembly (D) the interactions responsible for the formation of structures or patterns between components only occur if the system is dissipating energy. The patterns formed by competition between reaction and diffusion in oscillating chemical reactions are simple examples; biological cells are much more complex ones. Nowadays, most research focus on these two types self assembly, especially static self assembly. George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Types of Self-Assembly (Cont’d)
Two future variants of self assembly Templated self-assembly (T) interactions between the components and regular features in their environment determine the structures that form. Crystallization on surfaces that determine the morphology of the crystal is one example; crystallization of colloids in three-dimensional optical fields is another. biological self-assembly (B) is the variety and complexity of the functions that it produces. These two types of self assembly are defined here for the future. Because these two system are complicated but can be predict that they maybe more useful and powerful than the first two in the future. George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Examples of static self-assembly
(A) Crystal structure of a ribosome. (B) Self-assembled peptide-amphiphile nanofibers. (C) An array of millimeter-sized polymeric plates assembled at a water/perfluorodecalin interface by capillary interactions. (D) Thin film of a nematic liquid crystal on an isotropic substrate. (E) Micrometer-sized metallic polyhedra folded from planar substrates. (F) A three-dimensional aggregate of micrometer plates assembled by capillary forces. George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Examples of dynamic self-assembly
(A) An optical micrograph of a cell with fluorescently labeled cytoskeleton and nucleus; microtubules (~24 nm in diameter) are colored red. (B) Reaction-diffusion waves in a Belousov-Zabatinski reaction in a 3.5-inch Petri dish. (C) A simple aggregate of three millimeter-sized, rotating, magnetized disks interacting with one another via vortex-vortex interactions. (D) A school of fish. (E) Concentric rings formed by charged metallic beads 1 mm in diameter rolling in circular paths on a dielectric support. (F) Convection cells formed above a micropatterned metallic support. The distance between the centers of the cells is ~2 mm. George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Common features of self assembly
Self-assembly reflects information coded (as shape, surface properties, charge, polarizability, magnetic dipole, mass, etc.) in individual components; these characteristics determine the interactions among them. The design of components that organize themselves into desired patterns and functions is the key to applications of self-assembly.

Common features of self assembly (cont’d)
The components must be able to move with respect to one another. Their steady-state positions balance attractions and repulsions. Molecular self-assembly involves noncovalent or weak covalent interactions (van der Waals, electrostatic, and hydrophobic interactions, hydrogen and coordination bonds). In the self-assembly of larger components--meso- or macroscopic objects--interactions can often be selected and tailored, and can include interactions such as gravitational attraction, external electromagnetic fields, and magnetic, capillary, and entropic interactions, which are not important in the case of molecules.

Because self-assembly requires that the components be mobile, it usually takes place in fluid phases or on smooth surfaces. The environment can modify the interactions between the components; the use of boundaries and other templates in self-assembly is particularly important, because templates can reduce defects and control structures.

Equilibration is usually required to reach ordered structures. If components stick together irreversibly when they collide, they form a glass rather than a crystal or other regular structure. Self-assembly requires that the components either equilibrate between aggregated and non-aggregated states, or adjust their positions relative to one another once in an aggregate.

Why do we have special interests in self assembly?
First, humans are attracted by the appearance of order from disorder. Second, living cells self-assemble, and understanding life will therefore require understanding self-assembly. The cell also offers countless examples of functional self-assembly that stimulate the design of non-living systems. Third, self-assembly is one of the few practical strategies for making ensembles of nanostructures. It will therefore be an essential part of nanotechnology. George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Why we have special interests in self assembly?
Fourth, manufacturing and robotics will benefit from applications of self-assembly. Fifth, self-assembly is common to many dynamic, multicomponent systems, from smart materials and self-healing structures to netted sensors and computer networks. Finally, the focus on spontaneous development of patterns bridges the study of distinct components and the study of systems with many interacting components. It thereby connects reductionism to complexity and emergence George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Advantages of self assembly
First, Practicality it carries out many of the most difficult steps in nanofabrication--those involving atomic-level modification of structure--using the very highly developed techniques of synthetic chemistry. Directed assembly of nano-structures is time-consuming and impractical. Crommie et al, Science, 1993 George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Again, Practicality it carries out many of the most difficult steps in nanofabrication--those involving atomic-level modification of structure--using the very highly developed techniques of synthetic chemistry. Creating complex 3D structures on nanometer scale may be “impossible” using directed assembly. Rochefort, George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Second, it draws from the enormous wealth of examples in biology for inspiration: self-assembly is one of the most important strategies used in biology for the development of complex, functional structures. George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Third, it can incorporate biological structures directly as components in the final systems. George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Fourth, Accuracy because it requires that the target structures be the thermdynamically most stable ones open to the system, it tends to produce structures that are relatively defect-free and self-healing. Protein Image: Various protein structures. Protein Data Bank, George M. Whitesides etc, Science, Vol 295, Issue 5564, , 29 March 2002

Fifth, Energy Efficiency Nanometer scale assembly of structures is much more energy efficient than directed assembly. Hwang et al, Current Opinion, 2002

Directed vs. Self Assembly
Directed assembly Advantages Blue print is directly translated into a functional construct Disadvantages Costly Time consuming Performed at nonstandard conditions Instability may occur at standard operating conditions Self assembly Created and used in Standard conditions Concerted synthesis of structures Complex structures created with minimal intervention Method and models exist in nature Finding combination to complete a useful construct Morphological in this context basically means material shape.

Driving forces of self assembly
Assembly by capillary forces Assembly by electrostatic forces Assembly by magnetic forces Assembly by van der Waals Assembly by hydrophobic interactions Assembly by hydrogen and coordination bonds But, attention! There is no covalent bonds! Weak bonds

How self assembly works?
brick Function Strong bonds weak bonds How the self assembly works just like we use the brick to build mailbox, house and tower. The polymers we used for self assembly also have multiple usage. The bonds within polymer are strong bonds, but between polymers, they connect with weak bonds. Usually the products of self assembly have some special functions. The products of self assembly also can self assemble again and form large functional bodies. Weak intermolecular bonds, such as van der Waals bonds, that selectively bind molecules to a site in an assembly are what make Molecular Self Assembly (MSA) so varied. It would be almost impossible to mimic MSA complexity using synthetic, aggressive chemistry to join molecules together via covalent bonding. Although a covalent bond is much stronger, precursors, acidic/basic conditions, and high temperatures are required for chemical synthesis. For MSAs, synthetic chemistry is used only to construct the basic building blocks (that is, the molecules), and weaker intermolecular bonds are involved in arranging and binding the blocks together into a structure. This weak bonding makes solution, and hence reversible, processing of MSAs possible. Living things, planet, cosmos or polymer supramolecular

Roles it plays in nature
Self-assembly can occur spontaneously in nature, for example in cells (such as the self-assembly of the lipid bilayer membrane) and other biological systems, as well as in human engineered systems. It usually results in the increase in internal organization of the system. The world was created by self assembly!

Roles it plays in technology
Self-assembly is a manufacturing method used to construct things at the nanometre-scale. Many biological systems use self-assembly to assemble various molecules and structures. Imitating these strategies and creating novel molecules with the ability to self-assemble into supramolecular assemblies is an important technique in nanotechnology. Self-assembly involves a chemical process called convergent synthesis. Microchips of the future might be made by molecular self-assembly. An example of self-assembly in nature is the way that hydrophilic and hydrophobic interactions cause cell membranes to self assemble.

Applications Crystallization at All Scales.
Robotics and Manufacturing. Nanoscience and Technology. Microelectronics. Netted Systems. The self assembly can utilize in many fields.

Examples Mesoscopic metal-polymer amphiphiles by self assembly
Design nanotubes by molecular self assembly Enhancing Drug Function by self assembly

Self assembly of mesoscopic metal-polymer amphiphiles
Au-Ppy rods with a 1: 4 Au-Ppy rods with a 3:2 These are several SEM photos of the gold polymers by self assembly. (A) SEM images of Au-Ppy rods. The bright segments are gold, and the dark domains are polypyrrole, corresponding to the diagram in the upper right inset. (Lower right inset) A zoom-in image of a single rod, showing the difference in diameter for the two different blocks. (B) SEM images of assemblies of Au-Ppy rods with a 1: 4 block-length ratio (left), and a zoom-in image, revealing the highly oriented amphiphilic rods (right). (C) A SEM image of aggregates formed from Au-Ppy rods with a 3:2 block length ratio. (Inset) An optical microscopy image of a three-dimensional tubular superstructure formed from these rods. (D) A SEM image of a tubular assembly of Au-Ppy rods with a 4:1 block length ratio. (E) (Left) Optical images of a planar assembly of three-component rods (Au-Ppy-Au). (Inset) A side view of the planar assembly. The bright segments are Au, and the dark domains are Ppy. (Right) SEM images of the planar aggregates. (Inset) A zoom-in image of the planar assembly (top-down), showing their close packing. A side view shows the highly oriented Au and Ppy domains represented by bright and dark segments, respectively. (F) A schematic representation of the Au-Ppy-Au three-component rods. Au-Ppy-Au Sungho Park etc, Science, Vol 303, Issue 5675, , 16 January 2004

In a typical experiment, segmented metal-polymer rods were prepared by electrodeposition of gold into porous aluminum templates followed by electrochemical polymerization of pyrrole. The length of each block can be controlled by monitoring the charge passed during the electrodeposition process After the rods have been formed, they are released from the template by dissolving it with 3 M NaOH. The rods are centrifuged (5000 revolutions per minute for 10 min), rinsed several times with NANO-pure (Barnstead International, Dubuque, IA) water, and then resuspended in water by vortexing for 1 min. These materials have several unusual and potentially useful properties that make them promising for many potential applications in optics, electronics, and biodiagnostics. This slide shows the procedure how to use self assembly to get the mesoscopic metal polymer amphiphiles. Sungho Park etc, Science, Vol 303, Issue 5675, , 16 January 2004

For all rods generated for these studies, the average Au block diameter was 400 (±30) nm, and the polypyrrole block diameter was 360 (±25) nm. These structures self-organize into mesoscopic architectures with unusual structures, including bundles, tubes of varying diameters, and sheets. For example, amphiphilic rods with an Au block length of 1.8 (±0.2) µm and a polymer block length of 8.8 (±1.3) µm form bundle structures (Fig. 1A). These structures have been characterized by SEM (Fig. 1A) and optical microscopy. About 70% of the rods make up the bundle structures, with the other 30% being freely dispersed in solution. Sungho Park etc, Science, Vol 303, Issue 5675, , 16 January 2004

Design nanotubes by molecular self assembly
Special properties of nanotubes With one hundred times the tensile strength of steel, thermal conductivity better than all but the purest diamond, and electrical conductivity similar to copper, but with the ability to carry much higher currents. It seem to be a wonder material. Possible commercial applications of nanotubes are quite wide ranging and include composites, electronics, actuators, displays, microscope probe tips, batteries, capacitors and fuel cells.

On a molecular scale, the accurate and controlled application of intermolecular forces can lead to new, previously unachievable, nanostructures. This is why molecular self-assembly (MSA) is a highly topical and promising field of research in nanotechnology today. The second example utilizes the hydrophilic and hydrophobic as the driving force to self assemble. Werner J. Blau etc, Science, Vol 304, Issue 5676, , 4 June 2004

This is another example to create nanobubes by molecular self assembly. Jonathan P. Hill, Science, Vol 304, Issue 5676, , 4 June 2004

Schematic illustration of a proposed mechanism for the formation of supramolecular graphitic nanotube of 1. (A) A bilayer tape composed of graphitic layers, connected by interdigitation of the long (C12) alkyl chains. Each layer consists of bilaterally coupled 1D columns of -stacked HBC units. (B) A nanotube formed by tight rolling-up of the bilayer graphitic tape. Both the internal and external surfaces of the nanotube are covered by hydrophilic triethylene glycol (TEG) chains. (C) A helical coil formed by loose rolling-up of the bilayer graphitic tape. Jonathan P. Hill, Science, Vol 304, Issue 5676, , 4 June 2004

Enhancing Drug Function
(Top left) Endocytosis and transduction deliver the micelle-carried drug into the cell. From an esthetic perspective, it is attractive to build all desirable pharmacological features of a drug--such as solubility, stability, permeability to biological membranes, and targeting to particular tissues, cells, and intracellular compartments--into the drug molecule itself. But it would be simpler and perhaps more powerful to obtain these features by decoupling the biological action of the drug from the other biochemical and physicochemical characteristics that determine these key features of its pharmacology. Micelles are particularly attractive for drug delivery, because they do not require the chemical identity of the drug to be changed. The drug can be loaded into the core of the micelle, and the corona can be used to obtain several of the features listed above. Administration of micelle-incorporated drugs achieves several positive effects at once. On the level of the whole body, the drug is solubilized, avoiding use of the hydrophobic carriers usually used to deliver the drugs. On the level of the tumor and even its metastases, the leakiness of the tumor blood vessels (relative to the healthy blood vessels in most other organs) allows the colloidal particles to preferentially accumulate in the tumor (4). This reduces exposure to organs such as the heart. In the absence of a cell surface-binding ligand attached to the corona, the drug enters the cytoplasm mostly by diffusing out of the micelle and across the cell membrane. Diffusion across the membrane is possible as a result of the drug's hydrophobicity. This slow exposure to drug without cellular targeting can be highly effective--except when multidrug resistance is developed, in which a protein called the P glycoprotein pumps the drug from the cytoplasm back out of the cell. This problem can be partially overcome by grafting cell surface-binding ligands to the micelle corona, thereby inducing direct uptake into the cell by endocytosis, in which particles bound to the cell surface are internalized via membrane vesicles ("endosomes") (see the figure, top left panel) (5). The pH in the endosome is reduced via an active process, and eventually the endosome fuses with very low pH, enzyme-rich vesicles ("lysosomes"), which can degrade many drugs. The micelles presented by Savi et al. likely enter the cell by endocytosis, perhaps after nonspecific association with the cell surface (6). The micelle-incorporated small hydrophobic drug can then enter the cytoplasm at a much higher rate by diffusing across the endosomal membrane. The surfactant nature of the micelle-forming block copolymers may also enhance the permeability of the endosomal membrane or even disrupt it. The detection of micelles in the cytoplasm suggests that the latter mechanism is at least partially responsible. Whatever the mechanism, a higher rate of drug delivery to the cytoplasm is achieved, which may overwhelm the multidrug resistance efflux mechanism. Moreover, Kabanov and co-workers have demonstrated that ABA block copolymers containing poly(propylene glycol) can interfere directly with the function of P glycoprotein (7). Block copolymers of the class used by Savi et al. may also demonstrate this effect (8). Nanoscale polymer assemblies are also being developed for the delivery of plasmid DNA to the cytoplasm. In this case, as well as for delivery of gene expression-limiting ("antisense") oligonucleotides, permeability across the endosomal membrane plays an even more critical role. One of the most widely explored polymers for gene delivery is poly(ethylene imine) (9). This polymer is cationic at physiological pH and can therefore self-assemble with DNA by electrostatic interaction to form nanoscale polyelectrolyte complexes with diameters of 20 to 200 nm. These particles bind to the surfaces of cells, either by electrostatic interaction or via a more specific polymer-grafted cell surface-binding ligand. Upon endocytosis, the buffering capacity of the polycation leads to an osmotic pressure increase in the endosome, as proton pumps attempt to lower the endosomal pH. This osmotic imbalance increases the permeability of the endosomal membrane sufficiently to allow the escape of a fraction of the condensed DNA. To extend the concept of nanoscale assembly of polycation-DNA particles to the morphology of a micelle, Kataoka and co-workers have used graft copolymers of a polycation with poly(ethylene glycol) (10). The backbone of the graft copolymer condenses the DNA, and the poly(ethylene glycol) chains are forced into a corona, which stabilizes the assembly (see the figure, bottom panel). The resulting particles have a much narrower size distribution, limited toxicity, and improved stability of DNA against enzymatic attack compared to DNA complexed with the nongrafted polycation. Cell surface-binding ligands can be grafted to the tips of the chains forming the corona, leading to enhanced cellular uptake. Mechanisms have also been developed to disrupt the endosomal membrane even more specifically. For example, peptides that induce fusion or lysis of membrane vesicles (11) can be incorporated into such nanoscale assemblies. These agents are highly soluble at pH 7.4 and form amphiphiles as the pH in the endosome is lowered before lysosomal fusion. The amphiphiles then destabilize the endosomal membrane, allowing permeation of the incorporated drug. The micelle-mediated mechanisms described above involve endocytosis and subsequent endosomal permeation or destabilization. It may also be possible to use biological mechanisms to enter the cell through a pathway other than endocytosis. Some proteins, including the HIV TAT protein, contain "protein transduction domains," which cause the parent protein to cross the membrane directly (see the figure) (12). Attachment of such peptides to oligonucleotides and proteins induces their direct transport across the membrane in a manner that is not particularly sensitive to the molecular identity of the cargo. When synthetic, drug-conjugated polymers were decorated with the transduction domain peptide from the TAT protein, the polymers were directly transduced across the plasma membrane (13), without endocytosis or passage through the lysosome, carrying drug directly into the cytoplasm. Moreover, when surface-cross-linked micelles were similarly grafted with the TAT peptide, the micelle seemed to be transduced across the membrane as well (14). Much work remains to be done to develop polymer systems to direct diverse classes of drugs to particular cellular and subcellular targets. Yet, multifunctional polymer micelles have already come a long way to reaching these ends. Extrapolation of these ideas to vesicles (which enclose an aqueous core), rather than micelles, may permit larger molecules to be incorporated in a general way, independent of the identity of the molecule (15). Such systems may also provide unprecedented protection of the drug from biological degradation and denaturation before entry into the cell. (Top right) Micelle carrying drug molecules in its core. (Bottom) Polycation-DNA particle in the morphology of a micelle. Jeffrey A. Hubbell, Science, Vol 300, Issue 5619, , 25 April 2003

Enhancing Drug Function -some explanations
From an esthetic perspective, it is attractive to build all desirable pharmacological features of a drug--such as solubility, stability, permeability to biological membranes, and targeting to particular tissues, cells, and intracellular compartments--into the drug molecule itself. Micelles are particularly attractive for drug delivery, because they do not require the chemical identity of the drug to be changed. The drug can be loaded into the core of the micelle, and the corona can be used to obtain several of the features listed above.

Administration of micelle-incorporated drugs achieves several positive effects at once. On the level of the whole body, the drug is solubilized, avoiding use of the hydrophobic carriers usually used to deliver the drugs. On the level of the tumor and even its metastases, the leakiness of the tumor blood vessels (relative to the healthy blood vessels in most other organs) allows the colloidal particles to preferentially accumulate in the tumor. This reduces exposure to organs such as the heart. This slow exposure to drug without cellular targeting can be highly effective. thereby medicine inducing direct uptake into the cell by endocytosis, in which particles bound to the cell surface are internalized via membrane vesicles ("endosomes") (see the figure, top left panel) (5). The pH in the endosome is reduced via an active process, and eventually the endosome fuses with very low pH, enzyme-rich vesicles ("lysosomes"), which can degrade many drugs.

Much work remains to be done to develop polymer systems to direct diverse classes of drugs to particular cellular and subcellular targets. Yet, multifunctional polymer micelles have already come a long way to reaching these ends. Extrapolation of these ideas to vesicles (which enclose an aqueous core), rather than micelles, may permit larger molecules to be incorporated in a general way, independent of the identity of the molecule (15). Such systems may also provide unprecedented protection of the drug from biological degradation and denaturation before entry into the cell.

Homework Discuss from the John article why you think they form the shapes they do? What may cause them to twist as they do? Can you create a molecule that if it were to self-assemble would form a definitive three dimensional array? What are liquid crystals and does self-assembly play a role in their formation?

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