2002, University of Maryland biochemist Victor
Muñoz observed something about proteins
that challenged the generally accepted theory about
how proteins assume their biologically active states
- a process called folding. Muñoz suggested
that, in contrast to the belief that all proteins
fold in one sudden movement, some of them in fact
fold and unfold gradually, in a random series of
steps called downhill folding.
In the June 15 online issue of the journal Nature ,
Muñoz presents clear evidence of the potential
of his earlier observation. Using nuclear magnetic
resonance spectroscopy, which allowed detection of
protein folding events at the level of single atoms,
Muñoz and his team produced the equivalent
of a sequence of snapshots of the protein folding
process. Their findings could change the way scientists
look at proteins, the molecular nanomachines that
perform most of the body's critical functions.
"We found that some proteins do not fold like popcorn
exploding, but do it in a more gradual downhill folding
process that can be dissected with modern high-resolution
techniques," says Muñoz. "We were able to
see the folding process with such resolution because
we could stop it at a certain point, observe a property,
then move on to the next step. We can now ask specific
questions about the rules of protein folding."
Understanding protein folding could lead to the
ability to manipulate proteins to prevent disease,
such as Alzheimer's and Parkinson's Diseases, which
result when protein folding goes awry; create proteins
that could prevent crops from freezing; or even design
simple proteins that can be used as laundry detergent.
The Downhill Fold
protein must fold into a specific and unique three-dimensional
structure to be functional. The totally scrambled
protein and the finished 3-D structure are all scientists
have previously been able to see, which led many
to believe that folding was a one-step process. "Obviously,
the process had to be much more complicated than
that," says Muñoz. "The question was to find
the appropriate protein and methods to unveil all
this complexity. By analyzing individual atoms in
a downhill protein, we were able to resolve the structural
events that take place during folding."
Muñoz compares this process to figuring out
how a car is assembled. "It's very hard to understand
how a car is put together by just looking at all
the pieces in the storeroom or the complete car exiting
the assembly line. You don't know what the parts
do or how they are put together. But if you can look
at each step of the assembly process, then you have
the blueprint you need to build the car."
With a "Mess"
Muñoz's team looked at many atoms in the
folding process. "It looks like a mess at first,
but with sophisticated statistical tools, you start
to see exquisite patterns," says Munoz. You start
to see what is connected to what, how the folding
forces are acting to hold atoms together in space.
Confirming the atom-by-atom assembly process characteristic
of downhill folding gives us a new recipe for studying
Co-authors of the paper are Mourad Sadqi and David
Fushman, also of the University of Maryland. The
research was supported by grants from the National
Science Foundation and the National
Institutes of Health.
For a copy of the Nature article, see http://www.nature.com ,
or contact Katie McGoldrick, Nature Washington 202
737 2355; firstname.lastname@example.org .
Ellen Ternes, 301 405 4627 or email@example.com