A close-up view of an amyloid plaque model, showing the entangled structure of amyloid fibrils that form a sticky plaque. Image: M. Solar, MIT |
When
most people hear the word amyloid, they immediately think of
Alzheimer’s disease. And indeed, it was in the brains of Alzheimer’s
patients that these dense protein masses were first identified. But it
turns out that besides playing a role in a number of diseases, amyloids
also play an important structural role in many organisms from bacteria
to mammals, and might point the way to a whole new category of
biologically inspired synthetic materials.
Each
protein normally folds itself into a specific shape that governs many
aspects of its interactions with other materials and organisms. But
almost all proteins and peptides (organic molecules that are similar to
proteins but shorter) can alternatively form amyloids, which all have
the same essential structure but form dense, concentrated masses instead
of precisely folded shapes. These densely packed cores consist of
stacks of molecular structures called beta sheets, tightly bound
together by hydrogen bonds; a single “seed” of amyloid can induce many
of the nearby proteins to collapse into similar amyloid structures.
Now
Markus Buehler, an associate professor of civil and environmental
engineering at MIT, and Tuomas Knowles, a lecturer in physical chemistry
at the University of Cambridge in the U.K., have reviewed and analyzed
the details of how amyloids form, the different characteristics of
strength and adhesion that they can assume, and their potential as the
basis for new materials. Their analysis, encompassing both experimental
and computational approaches, was published July 31 in the journal
Nature Nanotechnology. The work was funded primarily by the Office of
Naval Research with additional support from the National Science
Foundation, the Army Research Office and the Air Force Office of
Scientific Research.
“Once
you form an amyloid, there’s no way back” to the normal protein shape,
Buehler says. Normal proteins naturally break down and their constituent
parts are recycled within a cell, but amyloids stubbornly resist that
breakdown — one of the features that give them their unusual strength as
structural materials.
Some
bacteria, such as the ubiquitous E. coli, produce amyloid-based
biofilms that help them adhere to surfaces or to other cells, even in a
liquid environment. “They are very sticky,” Buehler says. “They’re also
sticky in the brain, which is why they don’t break down easily. They
interfere with the functioning of tissues.” Concentrations of amyloids
within the human brain may play a role in the onset of Alzheimer’s
disease, Parkinson’s disease and other neurological conditions.
In
addition to their stickiness, amyloids are exceptionally strong and
resilient structures that can be used to form internal scaffolding to
support the structure of cells. Buehler and Knowles have analyzed in
detail the internal arrangement of amyloids, which involve a hierarchy
of structures at different scales—very similar, for example, to the
structure that gives silk its exceptional strength. Buehler compares
this hierarchical structuring to the way words, sentences and entire
books of great variety can be created from just a limited set of
building blocks in the form of letters of the alphabet.
Buehler
and Knowles found that the stiffness of most protein materials is
correlated with their position in an organism: The softest proteins such
as actin or intermediate filaments appear inside cells; stiffer
materials, such as collagen, occur just outside cells; and the stiffest
materials, such as bone or silk, typically form an exterior structural
skeleton. But amyloids are a notable exception to this rule, showing
exceptional stiffness even within tissues—which may contribute to their
role in promoting disease.
A
first step toward the exploitation of amyloids in engineering, Buehler
says, would be to produce protein materials with specific desired
attributes, such as structures that attach themselves to atoms of metal.
Then, these proteins could be induced to form amyloids that retain
these attributes. This process can be carried out “with very high
precision,” he says. “It’s much easier to control than protein folding.”
Buehler
says amyloids might be used to produce nanowires for use in highly
miniaturized circuits, and it’s even possible to produce more complex
structures such as coaxial nanowires—wires surrounded by conductive
cylinders, such as the cables used for television signals, which protect
currents running through them from electromagnetic interference.
Other
applications under development include the use of amyloid fibrils as
templates to control the orientation of polymers in new organic solar
cells, their use for controlled-release drug delivery, and for producing
three-dimensional scaffolding for tissue repair in the brain — a
remarkable turnabout of their destructive role in neurodegenerative
disease. Another potential application: adhesives resistant to solvents
as well as water.
Ehud
Gazit, professor of nanobiology and vice president for research and
development at Tel Aviv University in Israel, says this analysis is
“novel and remarkably important. As amyloids represent one of the most
fundamental structures in nature — both from the pathological point of
view as well as from the structural and functional one—true
understanding of the molecular basis of [their] mechanical properties is
central for biology and medicine.” The study of the molecular mechanics
of such structures “paves a new way for the understanding of other
ultra-rigid biological structures—[including] macroscopic ones, such as
spider silk, and microscopic ones, such as cytoskeleton,” he says.
Nanomechanics of functional and pathological amyloid materials