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THE dream of making enzymes to order has come a step closer with a computer
program that has designed one that catalyses a simple chemical reaction. In
future, such programs could be used to custom-build proteins that function as
enzymes to get rid of a particularly nasty type of toxic waste, for example, or
to break down fat. Ultimately, they might even make improved versions of the
enzymes in our bodies.

A protein molecule will only function as an enzyme if it is folded into
exactly the right shape to catalyse a particular chemical reaction. This makes
it hard to construct enzymes to order, because subtle interactions between amino
acids in the protein chain can have a huge effect on the shape of the folded
molecule.

One approach is to modify an existing enzyme by changing the amino acid
sequence a bit at a time, and then testing the resulting protein to see how well
it works. But this approach tends to be rather haphazard, so Stephen Mayo and
Daniel Bolon at the California Institute of Technology in Pasadena decided to
make it more systematic by using a computer program to choose which amino acids
are needed to catalyse a particular reaction.

The program is fed a description of the molecules involved before, during and
after the reaction. Based on these descriptions it figures out the shape an
enzyme would need to be to help the molecules along this path.

This description of the chemical reaction is fed into the program by way of a
three-dimensional model that gives the x, y and z coordinates of the molecules
involved, together with their respective charges.

Starting with the well-studied enzyme thioredoxin it adds or removes amino
acids to create a protein with the desired shape. The program uses basic
information about the structure and properties of individual amino acids to work
out how they will interact with each other and affect the shape of the protein
chain. The program runs through the most likely permutations, then chooses the
best contender. Finally, it spits out a list of amino acids in the original
enzyme that must be altered to create the designer molecule.

After that it is a relatively simple matter to construct the enzyme, by
changing the DNA that codes for the amino acids in the chain that need to be
swapped. The researchers harness the protein-making machinery of bacteria to
churn out copies of the designer enzyme.

So far they have made just two designer enzymes, both of which weakly
catalyse the breakdown of para-nitrophenyl acetate (PNPA) into
para-nitrophenol (PNP) and acetate ions. But Mayo says his program ought to
be able to design an enzyme for any chemical reaction.

While impressed with Mayo鈥檚 program, protein chemist Gregory Petsko of
Brandeis University in Massachusetts says that true success will come when the
computer can design enzymes to tackle more complex reactions than the
well-understood breakdown of PNPA. 鈥淣ature has had billions of years to perfect
enzymes,鈥� says Petsko. 鈥淚t is going to take us a while to catch up.鈥�