University of Washington (UW) Cyberscience Symposium Article
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Computing Structural Biology
With enough computing power, Dr. David Baker believes he and
other scientists could unlock the mysteries of structural biology by being able
to better predict and design macromolecular structures and interactions.
"This is the era of molecular biology", said Baker, UW associate
professor of biochemistry. "All of biology and medicine are being understood
in molecular terms - how the body works, what goes on with diseases, how
Understanding this would allow scientists to design better drugs
and treatments for major diseases such as AIDS and malaria and invent enzymes
that could catalyze novel chemical reactions, allowing, for example,
development of new methods for detoxifying poisonous substances in the environment.
To get there Baker needs more computing power and better
algorithms. "In principle, we should be able to compute all of structural
biology," Baker said. "If we could, it would be a fundamental test of our
understanding and have huge practical relevance."
Solving three-dimensional jigsaw puzzles
Baker is a world leader in efforts to predict the
three-dimensional structures of proteins from their sequences of amino acids. This
problem is considered one of the great challenges of modern biology. In blind
international challenges called CASP (Critical Assessment of Techniques for
Protein Structure Prediction), Baker and his colleagues have consistently proven
to be the best in the world.
Baker compares this challenge to
solving a three-dimensional jigsaw puzzle. Proteins begin as linear chains of
amino acids, but quickly fold into different three-dimensional shapes. These
shapes relate to their function and determine what other proteins they can
interact with and connect to.
While there are only 20 standard amino
acids, a protein can be made up of hundreds of them folding into vast combinations
of shapes. This presents a major computational challenge. To tackle it takes a
combination of sophisticated algorithms and intensive computing power. Baker and his colleagues have produced a
software program called Rosetta, which currently
is one of the most effective tools scientists have for sorting through the
possibilities to come up with a right answer.
Successful prediction and design
Baker is also working on predicting protein-protein
interactions, which are essential to most biological processes. In another
international blind challenge called CAPRI (Critical Assessment of Prediction
of Interactions) held in December 2004, Baker proved uniquely successful at
taking the structures of two proteins comprising a complex and then predicting
the structure of that complex.
Designing new proteins is another key effort of Baker and
his colleagues. Their article on this work recently won the 2003-2004 AAAS
Newcomb Cleveland Prize for an outstanding article in the journal Science.
Baker is now trying to design proteins that will be
functional and useful - such as improved vaccines for HIV - and creating novel enzymes
that will catalyze new chemical reactions. This last effort could lead to
better ways to detoxify poisonous environmental substances and make the
syntheses of complicated molecules easier and cleaner.
Additionally, Baker is trying to develop proteins that will
interact in novel and specific ways with DNA code, to do such things as
recognize and destroy DNA from pathogenic organisms or regulate how an organism
"We aren't there yet," Baker said. "But I can start to taste
the answer. We're getting closer."
Access to computing power
What Baker needs now is computing power. He believes that more
computing power could revolutionize the way structural biology is done. Currently,
structural biology is a completely experimental science requiring
millions of dollars in instrumentation.
"The revolution would be that you won't have to do
experiments to determine structural biology, you would be able to compute it." said
Baker, "It would be more elegant and cheaper."
The catch is that in order to prove this theory, Baker needs
the computing power. And he needs it on a scale found only at super-computing
centers like those in San Diego and Pittsburgh. Baker needs help to bring those
resources to the UW or, more likely, to get access to computing power housed
Future data center space
In the meantime, Baker is working on securing a larger
computer cluster. He's optimistic he will be able to get more machines, but if
this happens, he will need a place to house them.
Baker's current machines are in
the UW's central data center, operated by Computing & Communications at the
4545 Building, which soon will be out of capacity. In the near term, Baker is
looking to add 500 to 1,000 new machines. The building might have enough space to
house them, but Baker wonders about the future.
Data centers are highly
specialized environments with unique requirements including physical security,
electrical and HVAC (heating, ventilation and air conditioning) capacity, fire
detection and suppression, central monitoring, and more. Providing this capacity
is expensive. Baker said offering this type of specialized computing space is
one important way the university can help researchers. Demand for this space is
growing rapidly. "Biology will require a lot of computing," Baker said. "Housing
could become a real issue, and soon."
Expertise in global optimization is needed to improve Baker's
algorithmic approaches. Currently, he uses the Monte Carlo minimization method to
search for the most promising solutions. In this method, each processor carries
out an independent search. Baker thinks coordination between the searches could
be helpful. "How do you make this
search process the most efficient and how do you coordinate between searches,"
Baker said. "That's the challenging computational problem." Baker believes that
someone with expertise in global optimization could help.
Sharing UW expertise
Baker suspects that there are people with global optimization
expertise at the UW, if only he could find and engage them. The university has
some forums to help scientists reach across disciplines, but Baker said it
would be helpful to have more ways to connect people.
Additionally, the university could do more to promote interdisciplinary
study, for example, expanding joint advising of students by faculty in
different disciplines and then encouraging students to pursue that direction.
The future requires computing
The future of structural biology will involve computing at a
level not yet available, according to Baker. "With more computing power we
could solve these problems," Baker said. "I lie awake at night thinking about
how to get more computers."
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