New model brings USC chemists closer to 'holy grail' of catalyst design
keys are not supposed to fit the same lock, but in biological systems
multiple versions of a catalyst all make a reaction go, according to a
new study that explains the phenomenon.
Scheduled for online publication in PNAS Early Edition sometime after
Aug. 18, the study challenges entrenched ideas about the workings of
The study also suggests a method for designing new catalysts.
are molecules that speed up chemical reactions without participating in
them. Thousands of industrial and biological processes rely on
catalysts. In the human body, enzymes catalyze almost every reaction.
Holy Grail of enzyme catalysis and the ultimate manifestation of
understanding of this process is the ability to design enzymes," said
senior author Arieh Warshel, professor of chemistry at USC College.
listed drug production, environmental chemistry and bioremediation as
areas that could be revolutionized by custom-designed enzymes.
the PNAS study, Warshel described a computational model that both
explains a key aspect of catalyst function and suggests a design
Since the early days of catalyst chemistry, scientists
had championed the "lock and key" model, which held that a catalyst
worked by exquisitely surrounding and matching the reacting system (the
Warshel's group has published several papers in
support of an alternate theory based on electrical attraction.
According to the group, a perfect physical fit between catalyst and
substrate is not necessary.
"What really fits is the
electrostatic interaction between the enzyme active site to the
substrate charges at the so-called transition state, where the bonds
are halfway to being broken," Warshel said.
If Warshel is
correct, catalyst and substrate would be less like lock and key, and
more like two magnets: As long the opposite poles could get close to
each other, they would bind.
Warshel's model reproduced new
experimental data showing that a natural enzyme and its engineered,
structurally different counterpart both have the same catalytic power,
despite being very different from each other.
enzyme, made by co-author Donald Hilvert of ETH in Zurich, Switzerland,
displays less distinct folding than the natural enzyme. It also changes
shape very rapidly.
Warshel's model shows that the engineered
enzyme takes the shape of many keys, with all fitting electrostatically
in the same lock. This should offer a new option for enzyme design.
University of Southern California. August 2008.