A physicist working on cancer?

Make that an astrophysicist.

"I started out doing measurements on nuclear reactions that occur in the center of stars," says Ann Schmiedekamp, associate professor of physics at Penn State's Ogontz campus.

That was 20 years ago. In the course of raising four children and building an academic career alongside her husband -- also trained in physics -- Schmiedekamp has found it useful to be able to adapt.

In the late '70s, she began to work on some calculations for defining molecular structures by computer. One thing led to another, and for the last ten years she has collaborated with chemists at the National Cancer Institute in an effort to pin down the properties of triazenes, a class of compounds with potential for chemotherapy. By modeling triazenes on the computer, Schmiedekamp can complement experimental drug-development efforts, streamlining the route to what she hopes will be an effective line of anti-cancer treatment.

Her work relies on that pillar of physics known as Schrodinger's equation -- and on the number-crunching formidability of a Cray supercomputer. With these tools, Schmiedekamp does quantum-mechanical calculations on triazene molecules synthesized in the laboratory by a drug-design team headed by NCI's Christopher Michejda.

"Quantum mechanics," she explains, "predicts that an electron will behave as a wave as well as a particle. This wave behavior can be described by solving the Schrodinger equation." Thus, she can determine the structure of a molecule by solving the Schrodinger equation for its wave function. Without having to rely on experimental data, she can calculate a wave function that predicts many of the molecule's chemical and physical properties.

A triazene molecule has three nitrogen atoms, bonded together in what Schmiedekamp calls a kinked chain: two of the atoms are joined by a double bond, and the third is affixed by a single bond. When activated, a triazene will attach itself to a cell's DNA and destroy it, sundering the two strands of the familiar spiral ladder.

In order to become activated, the molecule has to break apart. The single nitrogen bond has to snap, leaving the highly-reactive double-bonded fragment exposed. And in order for that to happen, the molecule has to first pick up an extra proton from somewhere -- typically, says Schmiedekamp, from an acidic part of the cell.

To yield a triazene that is clinically effective, this decomposition process has to be controlled. "You want it to come apart at the right time, not prematurely," Schmiedekamp says. "So the stability of the single bond is key -- and that's what I've been working on."

That stability depends both on the conformation of the molecule -- its shape -- and on the triazene's substituents, the atoms that are bonded to the nitrogen atoms at either end of the chain.

"In some conformations, the bond breaks right away, as soon as the proton is added," says Schmiedekamp. "In others, it only stretches. It's weakened, but not broken."

That's where computer analysis comes in. "Calculations can determine the amount of energy necessary to push the molecule toward decomposition. The actual decomposition process happens too fast for the intermediate stages to be measured in the lab."

Schmiedekamp, in collaboration with Ogontz chemistry professor Judy Ozment and others, has done extensive calculations to find out which of a triazene's three nitrogen atoms is most likely to attach the extra proton. "Proton affinity," she notes, "is something that cannot be determined experimentally."

Currently, she is trying to determine -- given different substituents -- the precise levels of energy required for decomposition once the proton is in place.

As Michejda and his team synthesize larger, more complex molecules, Schmiedekamp's job grows correspondingly harder. A grant of 600 hours on the NCI's Cray supercomputer in Frederick, Maryland, has been crucial. To boost her analytical power even further, Schmiedekamp has worked to test a new class of computer codes that are faster than those in standard use.

That long-ago leap to computational chemistry, she says, wasn't so large a departure after all. "It's chemistry, yes, but really I'm working with physical concepts like the forces on atoms and the energy differences determined by quantum mechanical wave functions. Physics can have many applications."

Ann B. Schmiedekamp, Ph.D., is associate professor of physics at Penn State's Ogontz Campus, 1600 Woodland Road, Abington, PA 19001. Her work is supported by a grant from the National Cancer Institute.