Thu Oct 17 10:28:52 2002 Pacific Time

Quick-Change Artist: Tiny Protein
Folds Faster Than Any Other

GAINESVILLE, Fla., Oct. 17 (AScribe Newswire)
-- The world speed record for protein folding
apparently goes to an unusually tiny specimen
that traces its origins to Gila monster spit.

So reports a team of University of Florida
researchers in a paper published this week
in the online edition of the Journal of the
American Chemical Society. Though
significant mainly from a purely scientific
standpoint, the finding eventually may be
important in researchers' understanding
of the underlying causes behind
a host of maladies.

Proteins acquire their three-dimensional, blob-like
shapes when the amino acids they are composed
of spontaneously fold into place. The process
has become a hot topic in science in recent
years because the shape of proteins is directly
tied to their function in the cells of animals
and people. Misshapen proteins, or proteins
whose amino acids form an even slightly different
configuration than normal proteins, have been
connected to Alzheimer's disease and a range
of other serious disorders.

The UF team found the protein Tryptophan cage,
or Trp-cage for short, rockets from its
two-dimensional, line-like state of 20 amino acids
to its three-dimensional state in four-millionths
of a second. That's the fastest rate yet observed
for a complete protein - and about four times
faster than any other protein yet measured,
UF researchers say.

With about 10 atoms per amino acid, the protein
is composed of about 200 atoms, and each atom
must interact with every other atom before finding
its proper place in the structure. That means
at least 40,000 atomic interactions - pushing
and pulling movements - occur in an almost
imperceptible period, said Stephen Hagen,
an assistant professor of physics
and one of the paper's four UF authors.

"The fact that some proteins can fold incredibly
fast is really a remarkable thing," he said.
"What is it that's special about these molecules
that enables them to solve a very difficult
computational problem spontaneously
in such a short amount of time?"

Vijay Pande, an assistant professor of chemistry
at Stanford University, called the UF finding
"really important and very exciting." He said
it could speed up biologists' efforts to simulate
the protein-folding process, which could lead
to better drugs and cures for diseases
tied to misshapen proteins.

Scientists have long known that instructions
in genes' DNA determine the amino acid code
for proteins. However, they still don't know
the structure of most human proteins or the role
they play in many inherited traits or diseases.
The way amino acids come together to form
proteins is one area researchers are plumbing
for answers.

Enter the Gila monster.

Trp-cage stems from a protein another group
of researchers removed from the lizard's saliva
in an effort to understand why its bite makes
some people ill but not others, said Adrian Roitberg,
a UF assistant professor of chemistry.
The researchers modified the protein's structure
to make it more stable and easier to work with,
and then published the results of their work online,
where the UF scientists learned about them.

With other proteins composed of hundreds
or thousands of amino acids, Trp-cage's small size
might seem to explain its fast-folding speed,
but protein size and speed are not related,
Hagen said. More interestingly, researchers
expected Trp-cage would fold at least 1,000 times
slower than it does, leaving its blinding speed
"quite a mystery," Hagen said. There are two ways
of probing how proteins attain their shape:
experiments in the lab and computer simulations.
UF researchers have done both with Trp-cage.

Hagen's team, which included Roitberg
and UF physics doctoral students Linlin Qiu
and Suzette Pabit, used an advanced instrument
called a laser temperature jump spectrometer
to observe and time Trp-cage's transition
from its unfolded to its folded state.
Roitberg also was part of a separate team
collaborating with researchers from the
State University of New York- Stonybrook
that simulated Trp-cage's structure on a computer
based solely on its amino acid code.
The results, reported last month in the Journal
of the American Chemical Society,
caused a stir in the scientific community
because the simulated Trp- cage was extremely
close in size and shape to that of the actual
observed protein. If such a computational method
ever could be used to replicate larger,
more-complex human proteins, it could
speed the pace of research dramatically
because the laboratory experimental approach
is difficult, time consuming and expensive,
Roitberg and Hagen said. For now, however,
such a goal is far off, because computers
are not yet powerful enough to quickly process
all the information about each atom's forces
on all of the other atoms in larger proteins.

Roitberg's team's simulation of tiny Trp-cage
required 16 computers and three weeks
of computing time - another indication
of the protein's speedy folding rate.

Although protein fragments have been observed
to fold faster, the complete Trp- cage is one
of a kind. "Here's a molecule that is able to do
in four microseconds what it takes these
computers several weeks to do," Hagen said.

Hagen said many diseases are tied to misshapen
proteins. These include Alzheimer's, Parkinson's
disease, Mad Cow Disease and others, Pande said.

For biomedical researchers interested in genetic
therapy to correct these proteins' shapes,
that naturally raises the question of how proteins
mis-fold into botched versions. So while the news
about Trp-cage's folding pace has no immediate
biomedical application, it contributes to increasing
knowledge about this important process, Hagen said

NOTE: To view a slow-motion computer simulation
of the protein folding, please visit
http://www.napa.ufl.edu/2002news/ fastproteinph.htm

-30-

Media Contact:

Aaron Hoover,
UF Media Relations;
[log in to unmask]

Sources:

Stephen Hagen, Adrian Roitberg,
352- 392-4716, 352-392-6972;
[log in to unmask], [log in to unmask]

NOTE to EDITORS:
Image and computer animation available.

SOURCE:
AScribe - The Public Interest Newswire / 510-653-9400
http://www.ascribe.org/cgi-
bin/spew4th.pl?ascribeid=20021017.085737&time=10

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