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Biology is stuck in the past, according to Barry Honig, professor of biochemistry and molecular biophysics. "Molecules in biology rarely use advanced physics or chemistry to function," Dr. Honig says. "Instead, systems exploit simple rules from classical physics and chemistry."

Over his career, Dr. Honig has tried to understand how proteins exploit one branch of classical physics: electrostatics. His findings, incorporated into computer programs, have helped structural biologists see beyond the 3-D structure of their protein and predict how their protein works. GRASP, one of his successful programs, shows biologists where a protein is covered in negative and positive electric fields. Such information allows researchers to understand what can bind to proteins, such as other proteins or drugs.

But these programs depend on already knowing what a protein looks like and only a few thousand proteins so far have known shapes. In the last few years, Dr. Honig has turned to bioinformatics to help him predict unknown shapes from amino acid sequences. His new computer programs may become just as highly used as his old ones.

Dr. Honig began his academic career in chemical physics in the 1960s but quickly switched to biology after finishing his Ph.D. when he realized the physics problems that interested him were already well understood.

"The field of biology was exploding with fundamental questions," Dr. Honig says. "I became interested in the physical basis behind the eye's discrimination of color. The same small molecule that detects blue light also detects green and red light. How does it detect blue light in one situation and green in another?"

At the time, it was known the light-detecting molecule, retinal, was attached to a protein called rhodopsin in rod and cone cells in the eye's retina. Different rhodopsins exist for different colors of light, but retinal is always the same. Light is absorbed by the retinal molecule, which then activates rhodopsin, which in turn stimulates the rod or cone cell in which it is situated. Dr. Honig found that rhodopsin's electric field plays an important role in determining which color retinal initially detects.

After finding electrostatics' strong influence on visual proteins, Dr. Honig started to examine how electric fields affected the function of other proteins. Electrostatics turned out to be a general factor influencing many proteins, not just rhodopsin, and his lab developed a computer program, GRASP, so others could visualize a protein's electric field based on the molecule's shape and amino acids.

"Structural biologists run the program and the patterns help us understand how the protein functions," Dr. Honig says. "For example, a dimple with a negative field could be a binding pocket for a positively charged ligand."

But these programs depend on knowing a protein's shape, something that can take years to determine, even with time-saving advances in X-ray crystallography. Since many and perhaps most protein structures will never be solved experimentally, Dr. Honig has focused these past few years on methods to predict protein structure from amino acid sequences.

"Mostly we try to predict unknown structures by homology to other proteins that already have known structures," Dr. Honig says. The success of the strategy will depend on having enough known structures to make comparisons with.

About 10 centers in the country, funded by the National Institutes of Health's Structural Genomics Initiative, are trying to solve a large number of protein structures in the coming years. "The hope is to solve enough structures so that the rest of the proteins will be determined by homology," Dr. Honig says.

Homology modeling depends on aligning an amino acid sequence of an unknown structure with a similar amino acid sequence of a known structure. If the sequences are essentially the same, the protein shapes also will be essentially the same. Yet sometimes proteins with similar structures have dissimilar sequences and the sequences are hard to align.

"Usually, with dissimilar sequences, you end up lining a leucine up with a leucine, but those leucines may not be in the same location in the two structures," Dr. Honig says.

To improve sequence alignments, Dr. Honig first looks for clues in known structures. His new computer programs align related proteins so their backbones, binding sites, and other important spots match—sort of like aligning the structures of a Ford Taurus, Jeep Cherokee, and Lexus so the tires and steering wheels line up.

At the same time, the program highlights which parts of the amino acid sequences make the tires and the steering wheels. The sequences that code for tires may all be different, so the program inspects the sequences to find out if there are any patterns unique for tires. With a pattern in hand, Dr. Honig can then look for the tire pattern in another sequence whose structure is unknown and begin to construct a model.

"Once we have that structure," Dr. Honig says, "we can use electrostatics to ask how the protein functions. Two proteins may look the same but have different electric fields on the outside because they have different amino acids."

The lab is currently applying the new techniques to predict how protein domains influence the location of the protein inside the cell. Biology may be using rules from 19th century physics, Dr. Honig says, "but the rules are used really cleverly."