Dr. Carol Hall,
News Services, 919/515-3470
Simulation Shows How Fibrils – Proteins
That Cluster in Diseases – Form
NC State simulation shows randomly placed
peptides forming a fibril.
get a better look at how proteins gather into clusters
called amyloid fibrils – which are associated
with important human diseases such as Alzheimer’s,
Parkinson’s and the so-called prion diseases
like Mad Cow – researchers at North Carolina
State University decided to make movies.
Carol Hall, Alcoa Professor of chemical engineering
at NC State and Hung D. Nguyen, a graduate student
in Hall’s lab, used a computer simulation technique,
discontinuous molecular dynamics, to visualize the
meanderings of small proteins called peptides. Movies
of the simulation show that 96 randomly placed peptides
spontaneously aggregate into what Hall calls a “sandwich” of
layered protein sheets, similar to the amyloid fibrils
discovered in diseased people and animals. Hall says
that understanding how fibrils form in human or animal
organs may lead to discoveries of how to slow or
halt fibril formation.
research was published in the Nov. 16 edition of Proceedings
of the National Academy of Sciences.
is not known whether fibrils cause Alzheimer’s,
Parkinson’s and the other so-called amyloid
diseases, or whether they are just associated symptoms.
In any event, the fibrils form plaques in human and
animal organs, often the brain. Although it’s
not clear if these plaques cause memory loss in Alzheimer’s
patients, for instance, scientists are interested
in finding out the mechanisms behind the formation
of these diseases – Alzheimer’s, Parkinson’s,
ALS, Huntington’s – have the same unusual
phenomena. Proteins – completely different
proteins in each disease – assemble into ordered
aggregates, amyloid fibrils, so that a vital organ,
usually the brain, is crisscrossed by these structures,” Hall
said. “This tells us that the problem has something
to do with the general nature of proteins rather
than with the specifics of the particular disease-associated
studying fibrils in the test tube, researchers would
like to make computer models to view fibril formation.
This is not possible using the traditional atomic-level
protein folding simulation techniques – which
follow the motions of every atom on every protein – because
fibril formation takes a long time.
Hall and Nguyen developed a less-detailed model of
protein geometry and energetics and applied it to
a relatively simple protein, polyalanine, which had
been found to form fibrils in test tubes. With this
approach, the NC State researchers were able to watch
spontaneous fibril formation in about 60 hours on
a fast computer. That’s much quicker than atomic-level
the simulation movie, 12 to 96 peptides were initially
scattered randomly across the computer screen. When
set into motion, the researchers first saw groups
of two to five proteins coming together and falling
apart and eventually forming amorphous clumps that
twist around each other, like a rope. These twisted
structures began coming together, like the ingredients
in a sandwich, layered above and below each other.
In the end, the simulation showed a fibril-like structure
with only a few outlying peptides refusing to aggregate.
says her method of reducing the level of detail in
her protein model just to the point where the key
features that drive fibril formation remain and other
features are neglected allows her to get a broad
molecular-level picture of the fibril formation process.
work is sponsored by the National Institutes of Health.
She has recently been funded to attempt computer
simulations of fibril formation by beta amyloids,
the peptides that aggregate in Alzheimer’s
to editors: An abstract of the paper
Dynamic Simulations of Spontaneous Fibril Formation
By Random-Coil Peptides”
Authors: Hung D. Nguyen and Dr. Carol
Hall, North Carolina State University
Published: Nov. 16, 2004, in Proceedings
of the National Academy of Sciences
of normally soluble proteins into amyloid fibrils
is a cause or associated symptom of numerous human
disorders, including Alzheimer’s and the prion
diseases. We report molecular-level simulation of
spontaneous fibril formation. Systems containing
12-96 model polyalanine peptides form fibrils at
temperatures grater than a critical temperature that
decreases with peptide concentration and exceeds
the peptide’s folding temperature, consistent
with experimental findings. Formation of small amorphous aggregates precedes
ordered nucleus formation and subsequent rapid fibril growth through addition
of beta-sheets laterally and monomeric peptides at fibril ends. The fibril’s
structure is similar to that observed experimentally.