Nucleic acids, proteins, carbohydrates, and lipids are the biological macromolecules that form the basis of all life, from bacteria to humans. Barry Honig is advancing scientists' understanding of biology and medicine on a molecular level by developing tools to help predict the structure and visualize the interplay of macromolecules and to identify protein function. A great many scientists have taken advantage of these tools as they have pursued their own research.
The Human Genome Project led to the discovery of genes that orchestrate the production of tens of thousands of proteins, but the functions of most of these proteins remain a mystery. One important clue, however, may lie in their shape, because proteins interact with other molecules based on their three-dimensional configuration.
"It is still amazing to me that so many complex cellular processes ultimately can be understood in terms of the three-dimensional structures of biological macromolecules and their exploitation, for the most part, of simple principles of classical chemistry and physics," said Honig, who had planned a career as a chemical physicist but decided to switch his focus while completing a postdoctoral fellowship at Harvard University in the late 1960s.
This change of heart occurred when Honig became interested in the work of George Wald, a Harvard biology professor who had just won the Nobel Prize for discerning the physiological processes that underlie how our eyes "see." Honig, himself, was intrigued by how the eye discriminates among colors, and he set out to identify the physical basis of this phenomenon. He discovered that the electric field of the protein rhodopsin, found in rod and cone cells in the eye's retina, plays a key role in determining the color detected by the light-detecting molecule retinal. This finding laid the foundation for Honig's subsequent research.
Throughout his career, he has worked to understand how proteins take advantage of electrostatics—the positive and negative electric fields on their surface—to fold into intricate three-dimensional structures and bind to other proteins or cell membranes. Based on this work, Honig has developed computer programs to help structural biologists see past the structure of their proteins and predict how they might actually work. One program, called GRASP, shows the locations of the negative and positive charges that cover a protein's surface. This information helps researchers understand what other molecules or drugs can bind to a particular protein.
GRASP, however, presumes that scientists already know the structure of their protein, something that can take years to determine. Even with advances in x-ray crystallography, the technique used to determine protein structure, only a few thousand proteins have shapes that have already been determined. To get around this problem, Honig has recently turned his attention to predicting the shape of proteins based on their amino acid sequence.
When a protein's amino acid sequence is similar to the sequence in a protein of known structure, the three-dimensional structure of the known protein can be used as a "template" to infer the unknown protein structure. To advance this line of research, Honig has developed a variety of new computer programs. His current research also focuses on understanding the physical forces that lead proteins to bind to other proteins, membranes and DNA. He is particularly interested in how proteins are designed to recognize some macromolecules while avoiding others that are very similar in structure.
While Honig is devoted to his research, he admits to spending a great deal of time mentoring the students and postdoctoral fellows in his laboratory. "I enjoy seeing them develop into independent thinkers, and I'm delighted when they teach me something I didn't know or even anticipate," he notes. "I like to challenge the people in my laboratory… I tell them to apply high standards to everything they do and to question on a regular basis everything we and other researchers believe."
