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When viruses, bacteria, or other harmful invaders enter the blood
stream, the immune system fends them off by generating antibodies --
proteins shaped to latch onto the intruder (analogous to a lock fitting a
key) so that its ability to harm is immobilized. What if it were possible
to harness this remarkable ability to manufacture proteins matched to the
3D features of minuscule intruders? What about commercial applications?
Hmmm, said a few chemists about 30 years ago -- what about using the
immune system to generate catalysts, the substances that speed chemical
reactions?
 Laboratory work during the past 12 years has shown that
this once far-fetched idea is more than an idea -- catalytic antibodies
work. "The immune system can produce antibodies that bind to almost
anything," says UCLA chemist Kendall Houk. "It's really quite a marvel
this way. The idea is to use these proteins to catalyze reactions; after
all, nature uses proteins as enzymes to catalyze reactions in the body.
Maybe we can use antibodies to catalyze reactions that don't have
catalysts in nature."
For the pharmaceutical industry, catalytic antibodies offer
promise for rational drug design -- creating molecules with 3D features
sculpted to interact with other molecules. "Lots of synthetic chemists are
trying to develop methods to produce drugs with the proper
stereochemistry, the right 3D arrangement in space," says Houk. "One
possible use of catalytic antibodies would be to let 'nature' produce
these drugs."
 Houk leads a group of UCLA researchers who tackle
problems in organic and bio-organic chemistry, applying theory and
computation in conjunction with laboratory work. Catalytic antibodies are
one among a number of areas his group is interested in, with a focus on
understanding the atomic-level details of why chemical processes work the
way they do. "We've used the techniques of computational chemistry," he
says, "to elucidate what's going on in this hybrid of chemistry and
biology."
Although experiments with catalytic antibodies -- by several
research groups -- have have validated the basic idea, better
understanding is required for it to have practical value, says Houk.
"We're in a situation where we have exciting initial observations, but
frustrating lack of success in getting high acceleration of reactions.
They occur, but not well enough yet if we're going to use this for
something."
 With a series of computations
on SGI's CRAY Origin2000 at NCSA, Houk's group applied quantum mechanics
and classical molecular dynamics to illuminate how a particular catalytic
antibody speeds up a well-known organic reaction, called the Diels-Alder
reaction. Their results -- reported in Science (March 20, 1998) --
provide detailed new understanding of the interactions. The calculations
identify which 3D arrangement of transition-state molecules -- out of four
possible -- involved in the reaction binds with the antibody. They also
reveal for the first time that two separate hydrogen bonds -- formed
between the antibody and the transition state -- work together
synergistically to catalyze the reaction. "By doing calculations on how
that antibody binding-site interacts with the possible transition states,"
says Houk, "that's what tells us specifically what's going on."
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