A
tree outside Oak Ridge National Laboratory researcher Pratul Agarwal’s
office window provided the inspiration for a discovery that may
ultimately lead to drugs with fewer side effects, less expensive
biofuels and more.
Just
as a breeze causes leaves, branches and ultimately the tree to move,
enzymes moving at the molecular level perform hundreds of chemical
processes that have a ripple effect necessary for life. Previously,
protein complexes were viewed as static entities with biological
function understood in terms of direct interactions, but that isn’t the
case. This finding, published today in PLoS Biology, may have enormous
implications.
“Our
discovery is allowing us to perhaps find the knobs that we can use to
improve the catalytic rate of enzymes and perform a host of functions
more efficiently,” said Agarwal, a member of the Department of Energy
laboratory’s Computer Science and Mathematics Division.
Making
this discovery possible was ORNL’s supercomputer, Jaguar, which allowed
Agarwal and co-author Arvind Ramanathan to investigate a large number
of enzymes at the atomistic scale.
The
researchers found that enzymes have similar features that are entirely
preserved from the smallest living organism—bacteria—to complex life
forms, including humans.
“If
something is important for function, then it will be present in the
protein performing the same function across different species,” Agarwal
said. “For example, regardless of which company makes a car, they all
have wheels and brakes.”
Similarly,
scientists have known for decades that certain structural features of
the enzyme are also preserved because of their important function.
Agarwal and Ramanathan believe the same is true for enzyme flexibility.
“The
importance of the structure of enzymes has been known for more than 100
years, but only recently have we started to understand that the
internal motions may be the missing piece of the puzzle to understand
how enzymes work,” Agarwal said. “If we think of the tree as the model,
the protein move at the molecular level with the side-chain and residues
being the leaves and the protein backbone being the entire stem.”
This
research builds on previous work in which Agarwal identified a network
of protein vibrations in the enzyme Cyclphilin A, which is involved in
many biological reactions, including AIDS-causing HIV-1.
While
Agarwal sees this research perhaps leading to medicines able to target
hard to cure diseases such as AIDS, he is also excited about its energy
applications, specifically in the area of cellulosic ethanol. Highly
efficient enzymes could bring down the cost of biofuels, making them a
more attractive option.
Funding
for this research was provided by ORNL’s Laboratory Directed Research
and Development program. Ramanathan was a graduate student at Carnegie
Mellon University when this work began and now also works at ORNL.
UT-Battelle manages ORNL for DOE’s Office of Science.
Evolutionarily conserved linkage between enzyme fold, flexibility and catalysis