04.28.11 - Permalink
by Trish Barker
Researchers from Long Island University use NCSA's Abe to provide a valuable clue in the hunt for more effective antioxidants.
In the 1970s, Andreas Zavitsas had a theory that the key factor determining the rate of free radical reactions was the starting energy of the reactant, or parent, molecule. But other scientists, and their data, suggested that the variations of stabilities of transition states were most significant in determining reaction rate. And for about four decades, Zavitsas lacked the necessary computer power to carry out the demanding quantum mechanical calculations that could demonstrate whether his theory was correct.
Then came Abe. At last, Zavitsas and his colleagues in the Department of Chemistry and Biochemistry at Long Island University, Donald Rogers and Nikita Matsunaga, were able to show that variations in the ground state stabilities of the reactants can be as important in controlling how fast a chemical reaction proceeds. Their results were published in The Journal of Physical Chemistry A in October 2009.
"We are so appreciative that centers such as NCSA exist," Matsunaga says. "We run a relatively small research lab. It's very important for us to have access to computers such as Abe; it really changes how we do our research here."
Because they have unpaired electrons, free radicals are highly reactive loose cannons, capable of playing beneficial roles in important industrial processes, like combustion and polymerization, but also of causing cell damage in our bodies. That damage is linked to aging and disease, including Parkinson's, diabetes, and cancer.
"When a free radical reacts with a molecule, it forms another free radical, which reacts with another molecule to produce another free radical, and so on and on," explains Zavitsas.
"The same process keeps going around and around in a circle, a chain reaction, producing these free radicals. Which in abundance cause damage," says Rogers.
Tocopherols (which most non-chemists know as vitamin E) can dead-end that damaging chain reaction by quickly reacting with the original free radical to form a stable free radical that refuses to react and breaks the chain.
"We know experimentally that vitamin E is very good at trapping free radicals in the body," Zavitsas says. "They are good because they react with chain radicals very, very fast. And why vitamin E reacts with free radicals so fast goes back to the rate of reactions."
The question of what controls the speed of the radical reactions has been lingering for around 40 years, he says.
"We know that the reaction of vitamin E with chain radicals is very fast, but it is not clear that we understand why it's as fast as it is," Rogers says. "And that's very important, particularly in biological systems, because...the molecule that crosses the finish line is going to be the final product. The chain reaction that is carrying out a process that is implicated in carcinogenesis and in cell damage, if that is faster than the reaction of so-called sweepers (the tocopherols that make up vitamin E for example), you essentially have a kind of a race between the vitamin E and the free radicals. Which of those reactions wins out is the determining factor as to whether you're safe or unsafe."
For years, in trying to understand the factors affecting chemical reactivities, chemists had focused on variations of stabilities of transition states, the short-lived species atop the energy hill between reactants and products.
"People have focused in general on the height of the energy hill and on the structure of the molecules that are reacting on top of the hill," Zavitsas says. "We have suggested that one shouldn't only look at the structure at the top of the hill, but also look at the structure of what you're starting with."
The Long Island researchers examined benzyl fluoride with 11 common substituent groups in the meta and para positions; substituent groups are the atoms, or groups of atoms, that hang onto a hydrocarbon chain (in this case, a benzene ring) in place of a hydrogen atom, and para and meta are different positions where they can hang. They wanted to see how electron-donating and electron-withdrawing substitutents influenced the ground state molecular stabilization energy of the benzyl fluoride molecule and hence the activation barrier of benzylic fluorine atom abstraction by free radicals.
"We were interested in comparing the enthalpies [heat transfers] of benzylic molecules, which had very negative species attached to one end to those which had a very positive species attached to one end," Rogers says. "What we wanted to do was find out how the negativity or positivity influenced the energy of the molecule."
Using the G3 and G3(MP2) model programs on NCSA's Abe supercomputer, the researchers calculated the energies of the ground state and free radical transition state for benzylic abstractions from the 11 selected molecules.
"In order to calculate these very large energies, it takes a lot of computer time. And your computed results need to be very accurate, because you are looking for minute differences," Rogers says.
"It's like trying to get the weight of a captain of a superliner by weighing the superliner with and without the captain aboard," Zavitsas adds. "And these supercomputers make this possible. Just a few years ago, one couldn't do this at all."
"[Abe] is stupendously fast," Rogers says. "It's the fastest machine I could get my hands on! Any time you guys come up with a faster one, I'd like to get time on it!"
In addition to access to computing time, support for their research comes from the Whiteley Foundation and Friday Harbor Laboratories, University of Washington, which contributed research time and facilities. Their work is also supported by the Intramural Research Program of Long Island University.
Their calculations showed a strong correlation between the substituent's electron-withdrawing or -donating properties and the energy of the parent molecules, as measured by independent experimental methods.
"We found that the energy patterns fit very well with the rate patterns or the speed of reaction," Rogers says. "If you plot speed of reaction for this series of 11 molecules, and the energy of the ground state, you find that the patterns look almost identical. This leads to the conclusion that the rate of the reaction is predominantly determined by the energy of the reactant molecule."
Their conclusion is that when it comes to determining reaction rates, a narrow focus on the transition states without attention to the ground state stability tells only half of the story.
"Our work demonstrated that variations in the stabilities of the reactants can be as important in controlling how fast a chemical reaction proceeds," Rogers says.
Zavitsas says this reaction rate knowledge will be significant for researchers who are trying to make better free radical blockers. "Using knowledge about what controls the rate of free radical traps is the basis for trying to get something better."
This project was funded by Whiteley Foundation at the University of Washington and Long Island University.