tce

MATERIALS

Drugs, diagnosis and

electronics. Molecular
self-assembly is not
just for biologists, says
Tan Huey Ling

Molecules
and the art of
self-assembly
M

OLECULAR self-assembly,
ubiquitous in nature, is
emerging as a force to be
reckoned with not only in biology. Put
simply, the process takes a disorganised
system of components and, using the
components inherent properties and
interactions between them, forms an
organised structure all by itself.
A better understanding of how these
mechanisms work in nature has sparked
exciting developments in other areas
such as chemical synthesis, engineering,

These systems are attractive

because they can build
uniform, functional units or
arrays which can be exploited
at meso- and macroscopic
scale for both lifescience and
non-lifescience applications
(such as building nanowires
and high-energy-density
batteries).
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www.tcetoday.com march 2012

nanotechnology, polymer science, and

materials science.

a growing interest
Scientists across many disciplines have
become interested in molecular self-assembly
because it is key to understanding biology and
a variety of diseases at the molecular level.
In the last few years, advances in the use of
peptides (the building blocks of proteins)
have enabled the production of biological
materials for a wide range of applications,
including novel supra-molecular structures

CAREERS
MATERIALS tce
Figure 1 (right): At the University of Michigan,
scientists made biodegradable polymers that
could self-assemble into hollow, nanofibre
spheres. These spheres can be filled with
cells and injected into wounds to form a
support structure for the growing cells. Once
the cells are held in place, the spheres will
dissolved harmlessly.

and scaffolding for tissue

repair.
Today, the study
of biological selfassembly systems
is a rapidlygrowing field
that truly crosses
the boundaries
of existing
disciplines.
Self-assembling
systems range
from bi- and triUn
block copolymers to
ive
rsit
y of
complex DNA structures
Michi
gan
as well as simple and complex
proteins and peptides. These systems
are attractive because they can build
uniform, functional units which can be
used at meso- and macroscopic scale
for both lifescience and non-lifescience
applications such as building nanowires
and high-energy-density batteries.

oligopeptides the new

Lego?
A new class of oligopeptide-based
biological materials was accidentally

discovered by Shuguang
Zhang of Massachusetts
Institute of Technology
(MIT). Oligopeptides
(peptides
containing a
small number of
amino acids) are
short, simple to
design, extremely
versatile, and
easy to synthesise.
They have provided
insight into the
chemical and structural
principles of peptide selfassembly.
There are three types of selfassembling peptide systems.
Type I peptides form sheet structures
(a secondary pleated structure of protein)
in aqueous solution. Put simply, you could
visualise these as Lego bricks, with pegs
and holes, that can only be assembled
into particular structures. They consist of
alternating hydrophilic and hydrophobic
amino acid residues, which allow them to
form complementary ionic pairs within
each chain and/or between different chains.
While they have some of the common
features of uncharged peptides, such as
hydrophobicity and hydrogen bonding,
they also have unique charge properties
that can control how they aggregate. Adding
monovalent alkaline cations or introducing
the peptide solutions into physiological
media causes these oligopeptides to
spontaneously assemble into macroscopic
structures which can be fabricated into
various geometric shapes. Such structures
could be used to make new biologicallycompatible scaffolds for controlled drug
release, tissue repair, and tissue engineering.
Type II peptides can act as molecular
switches because they are made to selfassemble and disassemble by varying
conditions such as pH, temperature, or
crystal lattice packing. Theyve been studied
extensively because its hoped that better
understanding of the interactions between
these proteins will help us understand the
mechanisms and causes of some protein
conformational diseases, including scrapie,
Huntingtons, Parkinsons, and Alzheimers.
Type III peptides, like molecular hookand-loop fasteners, self-assemble onto
surfaces (rather than with each other) to
form monolayers. These oligopeptides
are useful as they allow a variety of other
molecules or specific cells to attach to their
end functional groups, and can thus be
used in testing and detection. The chemical
groups on the peptide can also react with
a surface anchor to form covalent bonds.
As such, biological surface engineering
march 2012 www.tcetoday.com

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MATERIALS

Self-assembly offers endless

opportunities and has a
significant future in a long
list of potential applications:
micro/optoelectronics,
catalysis, energy/magnetic
storage, biotechnology,
and novel materials which
adapt according to their
environment, to name a few.

is an emerging technology that will

provide new methods to study cell-to-cell
communication and cell behaviour for
tissue repair, immunity, and normal tissue
homeostasis.

new ways of working for

drugs
Many proteins and peptides are being
developed for use as drugs, but they cant
be administered orally, because they would
not survive the journey through the digestive
tract. This means they have to be injected,
which limits their use.
Macromolecular self-assembly could
provide a solution by engineering delivery
vehicles that make the drug both more
effective and easier to take.
Its possible to create a self-assembling
material for encapsulation and drug
delivery that has all the advantages of
the conventional cross-linked materials
normally used for controlled release. These
materials can be designed to self-assemble
spontaneously (or in response to an external
stimulus) and be tailored to have specific
properties set by the monomer they are
made of (see Figure 1).

In some cases its also possible to form

the drugs active pharmaceutical ingredient
when self-assembly is triggered, which
allows precise control of the concentration
of the active pharmaceutical ingredient
within the carrier and this can be a real
advantage.
There are benefits to be had for drugs
delivered via blood vessels too the
delivery vehicle can increase the drugs
circulation half-life (a measure of how long
it stays in the body), and in some cases,
target it at a desired tissue. Better delivery
and targeting could lead to reductions
in dose concentrations and frequency of
administration, which in turn could reduce
side effects.
To date, molecular self-assembly has
mostly been used to create drug delivery
vehicles chiefly micelles and vesicles
made from lipids and polymers. However,
we can also use self-assembly to build
other structures such as tubules, fibrils,
or complex systems such as microspheres
and molecular hydrogels (see Figure 2 for
examples of some common self-assembling
monomers).

Common self-assembling monomers include lipids, block copolymers, peptides and proteins. Intermolecular interactions that
drive and define self-assembly include hydrophobic association and the formation of polar interactions, respectively. The resultant
structures formed through self-assembly are shown. The hydrophilic portions are coloured blue and hydrophobic portions orange.

Monomers

Molecular interactions

Lipid

Electrostatic
interactions

Self-assembled structures
Spherical
micelle

Wormlike
micelle

+
H3N

H
O

Block copolymer

OH

Hydrogen
bonding

Vesicle
Vesicular tube

CH3

Peptide/protein

Micellar disk

H3C
H3C

CH3
H3C
CH3

Lamellar sheets

H3C

H3C
H3C

Sheet
Helix

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Hydrophobic
interactions

Fibrillar networks

Source: Monica C. Branco and Joel P. Schneider, University of Delware, Newark.

Figure 2: common self assembling monomers

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bugs to electronics
Another and somewhat surprising key
research direction involves using peptide
and hybridpeptide (a peptide-inorganic
material macromolecule) building blocks to
make metallic nanowires. This would make
it much easier to synthesise and modify large
quantities of these simple building blocks.
We already know that various types of
peptide nanotubes can form 1D metal
assemblies (eg glycylglycine bolaamphiphile
peptide nanotubes and peptide-amphiphile
nanofibres). These fibres are formed by selfassembly of hydrophilic peptides that are
joined to a hydrophobic aliphatic tail.
More complex assemblies such as
bacteriophages and viruses can also be used
as an organicinorganic template. These
viruses, self-assembled at the nanoscale,
are very effective as seamless templates for
making various inorganic materials.
Filamentous bacteriophages are
particularly effective, as they contain various
protein motifs (including single-chain
antibodies) on their surface, a technique
known as phage display. This technique,
which is widely used for selecting various
peptide-binding motifs (cataloguing signals,
that direct the recombinant proteins to
incorporate on the bacterial cell surface),
has been used to select peptide motifs
that can bind various inorganic metallic
and semiconductive nano-particles.
These phages can then be aligned to form
macroscopic metal or semiconductive wires.
Such wires were recently used in a
demonstration to produce electrodes for
thin lithium-ion batteries. By binding gold

s-layers to semi-conductors
Nano-structures of ordered s-layers
(bacterial surface layer proteins) could be
used in nanolithography, a technique used
to make semiconductor integrated circuits
(see Figure 4).
Purified s-layer building blocks
spontaneously reassemble into well-ordered
2D crystals under in vitro conditions. This
property has been used to show that its
possible to recrystallise s-layer sub-units
on various substrates that are suitable for
nanofabrication, such as silicon or silicone
oxide wafers. Bio-mimetic surfaces built
with s-layers are stable even when exposed
to strong solvents or extreme temperatures.
However, a much more controlled and
specific way of making highly ordered
nano-patterned affinity matrices is to use
genetic construction methods to tune the
functional and structural features of s-layer
fusion proteins. Diagnostic tools, vaccines,
or biocompatible surfaces, as well as specific
bio-mineralisation strategies have all been
developed in this way.

Figure 3: Northwestern University

researchers recently made a breakthrough
when they demonstrated the ability to
cause nanorods made from gold and
polymers to self-assemble into complex
shapes, including this sphere.
Chad Mirkin, Northwestern University

Self-assembly is also proving its worth as a

practical tool in diagnostics, where biological
materials are detected and quantified
using techniques such as immunological
recognition assays, enzymatic reactions, and
DNA- or RNA-based technology.
Diagnostic immunoassays include
products such as home pregnancy testing kits
that contain antibodies which detect minute
traces of the human chorionic gonadotropin
(hCG) hormone. Other products include
diagnostic kits for HIV or hepatitis virus
infections.
There are high hopes that using nanoscale assemblies and fabrication could
significantly improve the sensitivity as well
as the specificity of the diagnosis process.
Through better understanding and by
miniaturising the detectors and molecular
markers in such kits, it should be possible
to make them more sensitive and efficient.
This means that tests for key biological
parameters such as glucose levels could be
done on smaller blood samples, for example.

to the viruses and then reducing the cobalt

ions, researchers at Northwestern University
in the US created composite wires that
contained both cobalt oxide and gold.
Because these wires have very good specific
capacity, they make superb electrodes for
very energy-dense batteries (see Figure 3).

Chad Mirkin, Northwestern University

testing testing

high hopes, big challenges

Self-assembly offers endless opportunities
and has a significant future in a long list
of potential applications such as micro/
optoelectronics, catalysis, energy/
magnetic storage, biotechnology, and novel
materials which adapt according to their
environment, to name a few.
Not least of these is the prospect of selfassembling nano-machines. While these
are nothing out of the ordinary in nature (eg
functional molecular components of living
cells) the challenge is to mimic the idea and
use it in practicable technology. An obvious,
life-changing example would be nanomachines which could seek out and destroy
cancerous cells in the body, or detect defects
and blockages in organs or blood vessels.
While recent studies have brought a
degree of understanding of peptide selfassembly at the molecular level, our biggest
challenge now lies in figuring out how
we mimic this process systematically and
consistently. When we can do this, the
possibilities are endless. tce

Figure 4: Scientists at HP Labs have

produced a conductive wire 10 atoms
wide by vapourising erbium onto a silicon
surface. Such grown wires could become
the basis of the crossbar architecture that
HP has advocated as an alternative method
of making semiconductors.

Tan Huey Ling (hueyling@salam.uitm.

edu.my) is an academic researcher in the
chemical engineering faculty at Malaysias
Universiti Teknologi MARA
march 2012 www.tcetoday.com

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