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chemist is far from satisfied with what nature offers, at least when it comes to molecules. On a low-slung coffee table lie eight
toy-sized, 3D-printed replicas of proteins.
Some resemble rings and balls, others tubes
and cagesand none existed before Baker
and his colleagues designed and built them.
Over the last several years, with a big assist
from the genomics and computer revolutions, Bakers team has all but solved one
of the biggest challenges in modern science:
figuring out how long strings of amino ac-
Published by AAAS
vision. Though both his parents were professors at UWin physics and atmospheric
sciencesBaker says he wasnt drawn to
science growing up. As an undergraduate
at Harvard University, Baker tried studying
philosophy and social studies. That was a total waste of time, he says now. It was a lot of
talk that didnt necessarily add content. Biology, where new insights can be tested and
verified or discarded, drew him instead, and
he pursued a Ph.D. in biochemistry. During
a postdoc at the University of California, San
Francisco, when he was studying how proteins move inside cells, Baker found himself
captivated instead by the puzzle of how they
fold. I liked it because its getting at something fundamental.
In the early 1960s, biochemists at the
U.S. National Institutes of Health (NIH) recognized that each protein folds itself into an
intrinsic shape. Heat a protein in a solution
and its 3D structure will generally unravel.
But the NIH group noticed that the proteins they tested refold themselves as soon
as they cool, implying that their structure
stems from the interactions between different amino acids, rather than from some independent molecular folding machine inside cells. If researchers could determine the
strength of all those interactions, they might
be able to calculate how any amino acid sequence would assume its final shape. The
protein-folding problem was born.
One way around the problem is to determine protein structures experimentally,
through methods such as x-ray crystallography and nuclear magnetic resonance (NMR)
spectroscopy. But thats slow and expensive.
Even today, the Protein Data Bank, an international repository, holds the structures of
only roughly 110,000 proteins out of the hundreds of millions or more thought to exist.
Knowing the 3D structures of those other
proteins would offer biochemists vital insights into each molecules function, such as
whether it serves to ferry ions across a cell
membrane or catalyze a chemical reaction. It
would also give chemists valuable clues to designing new medicines. So, instead of waiting
for the experimentalists, computer modelers
such as Baker have tackled the folding problem with computer models.
Theyve come up with two broad kinds of
folding models. So-called homology models
compare the amino acid sequence of a target protein with that of a templatea protein
with a similar sequence and a known 3D
structure. The models adjust their prediction for the targets shape based on the differences between its amino acid sequence
and that of the template. But theres a major
drawback: Todays experimental structures
can only serve as templates for about half of
SCIENCE sciencemag.org
nique first proposed in the 1990s by com22 JULY 2016 VOL 353 ISSUE 6297
Published by AAAS
339
NEWS
NEWS | F E AT U R E S
340
Published by AAAS
ILLUSTRATIONS: V. ALTOUNIAN/SCIENCE
Easily solved by
comparative modeling
X-ray
crystallography
100,528
Conserved
position
Coevolved
positions
Variable
position
Information can be
coded into protein
sequences, like DNA.
Antagonists bind
to a target protein,
blocking its activation.
Channels through
membranes act as
gateways.
SCIENCE sciencemag.org
Published by AAAS
341
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