created computational tools that can predict the fleeting structures of
iron-containing enzymes as they transform during chemical reactions. Many of
these temporary but critical structures have eluded capture through traditional
experimental methods such as X-ray crystallography.
Jorge H. Rodriguez, associate professor of physics, has
used computational quantum mechanics to model such structures, called reaction
intermediates. He calls this combination of biochemistry and quantum physics
“The quantum mechanical laws of nature that govern materials—which
have been extensively studied in condensed matter physics—also govern the
behavior of biochemical systems,” Rodriguez said. “During biochemical
reactions it is actually the interactions of electrons—tiny particles within
atoms—that largely dictates the efficiency and rate at which these reactions
By carefully tracking and calculating the electron
interactions, one can predict many physical and chemical properties of
molecules, including their geometric structures. The method has the potential
to determine the structural changes a biological molecule undergoes and the
intermediates formed during the reaction process, he said.
Rodriguez and his former graduate student Teepanis
Chachiyo recently predicted the structure of a reaction intermediate of the
enzyme methane monooxygenase as it spurs the conversion of methane into the
alternative fuel source methanol.
“Knowing the structure of a key reaction intermediate
in the methane to methanol reaction greatly helps in understanding the process
and may help with laboratory replication of the catalytic cycle of the
enzyme,” Rodriguez said.
The computational procedure and structure of the methane
monooxygenase intermediate are detailed in a paper in Dalton Transactions. This research was funded in part by a National
Science Foundation CAREER award to Rodriguez.
Large biological molecules have clouds of many electrons
whirling around them, and it had been difficult in the past to accurately
calculate and keep track of so many electron-electron interactions, he said.
Rodriguez and Chachiyo used algorithms run on powerful
parallel-processing computers that can compute key physical and chemical
properties of iron-containing enzymes. They also incorporated experimental
information obtained through a technique known as iron-57 Mössbauer
spectroscopy. Their methods include algorithms that accurately predict iron-57
spectroscopic parameters and can predict geometric structures that are compatible
with those parameters. The team also performed computational analysis of other
experimental techniques, including optical spectroscopy, to further validate
their results, Rodriguez said.
Many metal-containing enzymes, called metalloproteins, act
as catalysts to accelerate the rate of important biochemical reactions and are
of scientific interest. Rodriguez also chose to focus on metalloproteins
because areas within these molecules undergo changes in their magnetism during
reactions with other molecules, such as oxygen, based on changes in a property
of electrons called “spin.” Electrons can spin in two directions, up
or down. When electrons centered on the metals line up in certain patterns of
up and down spins, the part of the molecule involved in the reaction becomes
The concept of magnetic transitions has been studied
extensively in physics, but traditionally has only been looked at in
solid-state materials. The understanding that changes in the spin states
influence molecular function as they go through each step of a biochemical
reaction had not been explored much in biochemical research, Rodriguez said.
“Theoretical physicists may use experimental
information to understand at a fundamental level why certain biochemical processes
happen, and this is complementary to the work of biochemists,” Rodriguez
said. “Biochemists have already observed and understood many aspects of
catalytic processes, but we can take that understanding to a deeper
atomic-scale level. The kinds of computational methods we use and develop open
the door for predictions in an area of science where we had previously only
been able to describe what happened after experimental observation.”
Rodriguez next plans to apply his methodology to other
important biochemical reactions catalyzed by iron-containing enzymes.
“There is an entire class of metal-containing enzymes
for which there is no structural information about their reaction
intermediates,” he said. “With our methodology in place, as long as
we have spectroscopic information we can potentially predict these intermediate
structures that may otherwise be unattainable.”