Date=24.03.1991; Publication=Columbia_Missourian; Page=00; Book=zz;
by David Holman
SYBYL is bright, sexy, sophisticated and fascinating. She joined the M.U.
chemistry department last fall, and the professors and
graduate students are already competing for space in her appointment book.
SYBYL is a remarkable computer program that runs on the
department's new Silicon Graphics IRIS-4D computers. The combination of
hardware and software makes a powerful, state-of-the-art
molecular modeling system. Such a system enables researchers to construct
three-dimensional models of very complex molecules in the
computer and to look at them on the monitor screen from any desired angle.
This ability is especially important in biological chemistry
because the biological activity of very large molecules, such as enzymes
and proteins, depends upon both their chemical composition and
their shape. The Silicon Graphics system looks about like any personal
computer that you might see in any of thousands of business
offices. There is a keyboard, a mouse, a large-screen monitor. But instead
of a single central processing unit, the M.U. setup uses two
computers, which the chemists have named Castor and Pollux.
On a rainy day in September, graduate student Chris Horan has a date with
SYBYL. Horan is just learning the program. He uses the
mouse to draw a molecule on the screen. He doesn't have to draw each
individual atom because SYBYL knows the structure of common
atom groups that can be assembled into more complex molecules. A benzene
ring or an amino acid can be added with a click of the mouse
button. Horan's first drawing shows dots for atoms and lines for the bonds
between them, just like the drawings in your basic chemistry
textbook except the computer shows each element in a different color. He
selects the "optimize" function from SYBYL's menu, and his
molecule suddenly changes shape. SYBYL has computed the most stable
conformation for the chain of atoms that Horan constructed.
Another click of the mouse button and the drawing turns into a 3-D
stick-and-ball model. Click again and the actual surfaces appear. The
model now looks like a twisted mass of brightly colored fish eggs, stuck
together and floating in space. Horan moves the mouse across
his drawing pad and the molecule on the screen begins to rotate so he can
see it from a different angle.
It is also possible to put two molecules at a time on the screen to see
how they will "dock" or fit together during a chemical reaction. This
is one of SYBYL's most attractive features, but Horan hasn't figured it
out yet. He spends about half an hour experimenting with the
program, demonstrating different display modes, watching the basic
components of living things, a million times larger than life, twisting
and turning in computer space. He leaves the room smiling.
"It's hard to believe you're actually working when you're having this much
fun," Horan says. But molecular modeling is more than a
game of electronic Tinker Toys. It is only one aspect of a growing area of
study known as computational chemistry, and it's serious
"It's not only theoretically interesting now. It is commercially of use,"
says assistant professor Rainer Glaser, a computational chemist
and Horan's faculty mentor. "You will rarely find any of the major
companies in America that do not have a theoretical chemistry group
with molecular modeling."
The main applications for this technology are in pharmaceuticals,
agricultural chemistry and diet foods. Research in these areas involves
creating thousands of compounds and testing them for their biological
activity to see if they do produce the desired effect in an organism.
It would be nice if a chemist could predict a compound's biological
activity before synthesizing it, rather than testing for it after the
but this is hard to do.
Life is a continual remodeling process controlled by programs encoded in
an organism's genes. All living things are complicated chemical
factories that are constantly building large molecules in some locations
and taking them apart in others--digesting food, building new
tissue, fighting infection, removing waste products and sending messages
back and forth to keep the factory running smoothly. Many of
the chemical reactions that occur in living cells are turned on and off by
a sort of lock and key mechanism. Large protein molecules called
receptors, found on the surface of special cells, act as the lock. Each
receptor is twisted into a unique shape, a sort of keyhole that
protects a reactive site within the receptor. The lock can only be opened,
and the reaction turned on, by a messenger molecule with the
correct shape to fit into the protein keyhole and thus reach the reactive
site in the receptor.
The search for new drugs, pesticides, and other biologically active
compounds is often a game of chemical lock picking. Researchers
look for compounds that will either mimic an organism's natural keys and
turn on a reaction or block the key hole to prevent the
organism's own keys from working. A successful compound should have the
desired biological activity without affecting other reactions
and causing undesirable side effects. Trial and error, the traditional
research method, is extremely expensive and time-consuming. It's
like shooting craps, but the odds are worse. Molecular modeling can
improve the odds by letting the researcher examine the shape of the
key before it is actually made. A theoretical chemist can test an idea for
a new compound with a computer modeling program and, in a day
or two, have a fair idea of the compound's biological activity. To
synthesize and field test the same compound might take a team of
chemists a year or more.
Molecular modeling is a powerful tool, and several programs are now
available, but it does have its limitations.
"If it did exactly what it purports to do, we could just have one chemist
synthesizing only those compounds that are suggested by the
program," says Grant Dubois, director of a new products research team at
NutraSweet Co. "But in reality, things don't work that way."
Dubois says his company employs two full-time computational chemists and a
molecular design team. They have been using molecular
modeling programs for several years, but Dubois is not putting all his
eggs in the modeling basket. "We use a variety of methodologies,"
he says. He apparently hasn't forgotten that aspartame, the sweetener that
made NutraSweet Co. possible, was discovered by
pharmaceutical researchers who were looking for something entirely
different at the time. A slavish adherence to models, or any other
regimen, doesn't leave much room for serendipity. And sometimes the models
are wrong, especially in taste perception, where the nature
of the receptors is not yet well understood.
There is nothing inherently wrong with molecular modeling. As with any
computer model of any complex system, its weakness comes
from the same source as its strength--the assumptions on which the model
Seated in a squeaky wooden swivel chair, which seems oddly anachronistic
in his computer-filled office, Rainer Glaser gets to the root of
the problem. Getting down to basics is his specialty. He computes the
energies and structures of molecules ab initio, from the beginning,
using the laws of quantum mechanics.
"If you do calculations ab initio, you can be very certain that you have a
model that's very close to the real thing, whether you are doing a
known molecule or an unknown molecule," he says. But very large molecules,
such as proteins, which may contain hundreds of atoms,
cannot be computed using quantum chemistry. The calculations are simply
too overwhelming, even for a big computer.
"In the stuff we are doing here, sometimes we have little molecules that
have two nitrogens, an oxygen, a carbon and a couple of
hydrogens," Glaser continues, "and it runs for six days on our computer.
Just for one computation. You cannot compute these very large
molecules. Even if the computers grow in their speed, as they have in the
past few years, we will not be able to do that. Ever."
But the rigorous methods of quantum chemistry can be used to attack the
large molecules one small piece at a time. For example, a
hydroxyl group (one hydrogen and one oxygen atom) bonds to a larger group
of atoms in some characteristic fashion. The computational
chemist can calculate a standard length for that bond and a characteristic
energy curve. The modeler now has a set of parameters which
help to predict how the hydroxyl group will behave in other molecules.
"With molecular modeling we are not doing real quantum chemistry any
more," Glaser says. "We think of each bond between atoms as a
little spring with a certain force constant. We think of each angle in the
formation as having another force constant, just like a little spring.
These force constants we take from the ab initio computations and from
empirical observations, and we just fit them in the molecular
model so they reproduce what we already know. Then we assume that we can
use that to predict things that we don't know yet." But
parameters derived from known molecules may not always apply precisely to
unknown ones. So there is a cycle of constant improvement
that includes the theoretical chemist, the computer program writer and the
synthetic chemist. Each provides grist for another's mill, and
gradually the parameters are refined and the models become more accurate.
The field of computational chemistry is very young. It is concerned with
calculating the properties of molecules from principles of
quantum mechanics and then applying that knowledge to problems that arise
in other areas of chemistry. The basic theories of quantum
chemistry were worked out in the 1930s, but they could not be applied to
practical problems until recently, when computers became much
more powerful and much less expensive. Without computers the chemist could
not do the millions of computations required, and even if
the calculations could be done, nobody else could understand the results.
"All our results come in numbers," Glaser says, pulling a thick loose-leaf
binder from his desk. "This is what we get. Twenty-five, thirty
pages of numbers. Nothing else. This doesn't tell anybody anything unless
he is an expert. So we have to go into producing
graphics--surface plots, line plots, contour plots and the likes. This is
where the scientific work really starts, if you look at these
calculated results in the form of pictures."
Glaser leads a gallery tour of the graphic art that covers his laboratory
walls, talking about electron density and energy and gradient vector
field lines. A chemist may see these things. Others will see strange
spider webs, old lace, exotic flowers or butterflies, landscapes of alien
Computers and graphics programs like SYBYL have literally opened new
horizons for chemists--and scientists in every field. They are
bringing scientists exciting snapshots from unseen worlds, and travel
pictures seem to stimulate imagination and the desire for further
While Chris Horan looks for more examples of molecular art, Glaser stands
with one hand on his new VAX 3100 computer--1.2
gigabytes of memory in a box the size of a carry-on suitcase, computing
power that would have filled his entire lab ten years ago. He's
standing there and he's bitching, in a cheerful sort of way.
"Greed comes to every computational chemist," he says. "We never have
enough computer time. We always want more. We are still
doing relatively small molecular systems. There are so many areas of
chemistry that we can hardly touch because the computers just
aren't fast enough yet."
Copyright Columbia Missourian