Billions and Billions of Molecules

June 1, 2006

Twenty-first-century chemists may spend as much time pecking away at computer terminals as twiddling test tubes at the lab bench. They use computers to analyze data and simulate molecules, speeding their advances in molecular manipulation.

One dramatic example of this revolution is a new computer method Duke chemists are developing to sift through a near-infinite array of molecular possibilities to identify the best molecules for drugs, electronic devices, and other uses.

Their method would help address the daunting fact that "there aren't enough atoms in the universe to make all the reasonable-sized molecules that could be made," says David Beratan, R.J. Reynolds Professor of chemistry and department chair, a developer of the approach.

The Duke chemists published an article on their technique in an online issue of the Journal of the American Chemical Society. Other members of the team are chemistry professor Weitao Yang and postdoctoral fellows Mingliang Wang and Xiangqian Hu.

The computer-assisted sifting method basically calculates its way through an immense number of possible arrangements of molecular building blocks that the chemists define. They instruct the computer to search for arrangements with desired chemical or physical properties and to generate a kind of "landscape" of molecular possibilities in which the optimal compounds jut upward like Mount Fuji among its foothills.

"So for one such application, the 'peak' might be the perfect drug from the standpoint of binding to a protein," Beratan explains. "Down in the 'basin' would be other molecules that are average to poor from the standpoint of that application. And for each application there would be a different Mount Fuji at a different location in this space."

In such calculations, the computer uses a property called "linear combination of atomic potentials"--conceived by Yang's research group--that reflects the energy relationships between electrons and associated nuclei in the atoms of possible molecules. To recall freshman chemistry: Atoms consist of electron clouds surrounding the central nucleus. As atoms combine into molecules, electrons of neighboring atoms coalesce into bonds between the atoms.

In contrast to the new technique, says Beratan, chemists' current process of tweaking molecular structures a bit at a time to seek an ideal molecule can get "lost" in the huge space of molecular possibilities.

"For instance, all the current molecules related to aspirin may be in one place, while all the Tylenol-like molecules are in a separate cluster," he says. "Meanwhile, maybe the best possible drug of that type may be undiscovered somewhere else with a chemistry that's quantitatively different from known molecules."