Warshel Fêted by Royal Society of Chemistry

In 1963, a burning question kept invading the mind of a young kibbutznik studying chemistry at the Technion, Israel Institute of Technology, in Haifa.

Arieh Warshel had to know: just how do enzymes speed up chemical reactions?

The undergraduate began an experiment that eventually resulted in the first nuclear magnetic resonance (NMR) measurement of the fast step in the catalytic reaction of chymotrypsin. But he could not pinpoint the exact origin of the catalytic effect that speeds the reaction — yet.

“At that time I took a very intimidating class in quantum mechanics learning about the so-called impact parameter, at the physics department,” Warshel recalled. “The class was way above the level of what we were learning in chemistry, and the only part that I fully understood was the implication that asymptotic quantum mechanical wave functions — a function that describe the quantum nature of the system at its initial and final states — can always solve any complex problem in physics.”

Warshel told his classmates that one day he would develop an asymptotic wave function for enzymes to understand how they work.

“Of course, I had not a clue what enzymes looked like and how a wave function would explain the action of enzymes,” Warshel said.

Years later, it was Warshel’s Empirical Valence Bond method (EVB) that captured the asymptotic features of enzymatic reactions. Led by Warshel, the 1976 landmark paper paved the way for quantitative studies of enzymatic reactions and facilitated the first consistent modeling of the catalytic effect of an enzyme. This work also introduced the hybrid Quantum mechanical/Molecular mechanics (QM/MM) method and a microscopic dielectric model that have represented the entire enzyme-substrate complex and the surrounding solvent. 

Regarded as the founder of computational enzymology, Distinguished Professor of Chemistry and Biochemistry Warshel has earned the 2012 Soft Matter & Biophysical Chemistry Award, presented by the Royal Society of Chemistry (RSC). The award honors the USC Dornsife professor for his numerous ground-breaking developments in computational biophysical chemistry — research that made possible the elucidation of protein structure/function relationships.

Formed in 1980, the RSC is a professional association based in the United Kingdom aimed at advancing the chemical sciences. The association opened with 34,000 members in the U.K. and 8,000 abroad.

During an awards ceremony on Nov. 28 at the University of Sheffield located in South Yorkshire, England, Warshel was presented his medal and citation by RSC’s Faraday Division Council President Graham Hutchings. The ceremony took place amid a three-day symposium, in which Warshel gave lectures at Sheffield, Newcastle University and the University of Bath.

“It’s nice to be recognized and I appreciate it very much,” Warshel said.

A research fellow at Harvard University, then a senior scientist at the Weizmann Institute of Science, in Rehovot, Israel, Warshel arrived at USC Dornsife in 1976. His early studies pioneered computer simulation of the action of biological molecules and his team continues to expand on the early progress in pushing the boundaries of molecular simulations, ranging from studies of enzymes that control key biological processes to the action of molecular motors and ion channels.

“There are many, many cases in which the structures of proteins have been solved,” Warshel said. “Scientists have solved the structures of almost every important biological system there is. So we have structure information about what it looks like. So what I’ve been doing since 1973 is trying to take the structure and ask how does this structure determine how the machine is working?

“Let’s say you have a protein that serves as an enzyme. It makes chemical reactions very fast. So when you know the structure of the protein, we still must know what about it makes it work so fast.”

He said for example, one may look at a clock and see that it looks nice but that person will still not know how the clock works.

“You cannot figure it out experimentally because you cannot send tiny people inside to explore,” he said, tongue-in-cheek. “At present, people don’t know how to do this. Thus we must do it by computer.

“So what we’ve done in the past 50 years is build models that allow us to put all of these atoms together on the computer and then to simulate how they do what they do and to understand what is responsible for each action.”

This field has many names, but can be classified as computer simulation of biological functions, part of computational biophysics.

“What counts is that we have enormous fun solving problems that tell us how nature works.”