Researcher's Efficient Calculations Allow Researchers To Predict Structure And Function Of Large Molecules

Peter Pulay, Distinguished Professor of chemistry and biochemistry, will present his findings this week at the Frontiers in Theoretical Chemistry conference in Okazaki, Japan.

Researchers seek knowledge of molecular structure because structure determines function, and changes in the structure can enhance or inhibit certain molecular properties. This relationship between structure and function may help biomedical researchers create designer drugs or discover the underlying mechanisms of a particular disease. If scientists know the atomic structure of a molecule, they also may be able to predict how it will behave in different situations -- and might be able to build a synthetic molecule that could mimic its natural counterpart.

But calculating the structures of all but the smallest molecules remains a daunting task, because the electron energies must be calculated with respect to one another to get an accurate structural picture. Because of the number of electrons buzzing around in each atom, the required calculations can take thousands of hours of computer time.

Pulay's method makes the calculation of structures of large molecules, like the cancer-fighting natural substance taxol with 113 atoms, feasible -- even on PC-based computers.

Pulay and his colleagues, including post-doctoral student L. Fust-Molnar, have developed a method to calculate electron density using the principles of Fourier transform nuclear magnetic resonance. Fourier discovered that most functions can be represented as the sum of sine and cosine waves. Using this principle, Pulay's team was able to cut the electron density calculation time down by about ten-fold.

"This will open up calculations for larger biological molecules," Pulay said. He and graduate student Irina Diaz-Acosta examined the structure of the active site on cytochrome p450, which takes hydrocarbons in the body and puts hydroxyl groups on them.

"This is how the body gets rid of some toxic substances," Pulay said. "People would like to know what makes this molecule tick."

Researchers also use computer modeling and calculations in atmospheric chemistry, where reactions can be almost impossible to simulate in a laboratory. Dilute gas reactions cannot be replicated in containers where the molecules hit walls. Thus, modeling becomes essential to learn about the interactions between molecules.

"There are many steps in the middle of a reaction that make it work, and many of these are unknown," Pulay said. A simpler method of calculating complex structures will bring researchers one step closer to "seeing" these interactions at work.

Pulay's research is supported by a grant from the National Science Foundation and by a grant from the Air Force Office of Scientific Research, upon which senior scientist Jon Baker is co-principal investigator.