U.Va.'s Wladek Minor is Putting Proteins on the Molecular Map

Wladek Minor
Photo by Tom Cogill

As recently as a decade ago, researchers hoping to visualize the structure of the pattern of atoms in a protein molecule spent months — even years — generating a three-dimensional (3-D) model. Even when a model was complete, it would often require lengthy and time-consuming validation to ensure against human and experimental error.

Enter Wladek Minor, a professor of molecular physiology and biological physics at the University of Virginia School of Medicine, whose inventive software has dramatically transformed the field of protein crystallography. Thanks to the software suites Minor and his colleagues have developed, researchers can now elucidate the structures of macromolecules, viruses and smaller molecules in as few as five to 10 minutes.

“By speeding up the process and making it easier for scientists to determine the molecular structures of protein crystals and whether they warrant further detailed studies, our software is significantly adding to the body of knowledge in many fields, leading to countless discoveries across the world,” Minor says.

The impact of Minor’s research has been tremendous. Together with Zbyszek Otwinowski, his former student, Minor has developed a successful start-up company, HKL Research Inc., that has commercialized the HKL software suites — HKL, HKL-2000 and HKL-3000, Minor’s most recent undertaking. More than 10,000 crystallographers and other scientific researchers worldwide have already benefited from the HKL software suites, which have been used to solve more than 70 percent of all reported protein structures. Having authored or coauthored more than 80 publications, Minor is perhaps best known for his 1997 paper, coauthored by Otwinowski, which introduced HKL-2000; reported in 2006 to have been the second-most-cited scientific paper of the past decade, the publication has garnered more than 15,000 citations to date.

In recognition of the undisputed value of his research, the U.Va. Patent Foundation named Minor the 2007 Edlich-Henderson Inventor of the Year. “The Patent Foundation’s Inventor of the Year Award recognizes a faculty inventor whose technology is of notable value to society,” says Robert S. MacWright, U.Va. Patent Foundation executive director and chief executive officer. “The numerous citations Wladek Minor’s research has received illustrate its importance in research, and society clearly has benefited from the insights his work provides to those developing new drugs and therapies destined for the patient’s bedside.”

Minor and his colleagues developed the innovative software in response to a challenge from the National Institutes of Health, whose Protein Structure Initiative seeks to make the 3-D atomic-level structures of most proteins easily obtainable from knowledge of their corresponding DNA sequences. Minor’s lab is a part of the Midwest Center for Structural Genomics, a leading center within the initiative, which has revealed the 3-D structures of more than 650 proteins.

The software visualization process begins with the use of an X-ray tool. Using X-ray diffraction data collected on protein crystals, the software first generates an electron density map — a 3-D pattern of the average density of electrons of all the atoms in the smallest nonrepeating unit of the protein crystal. Then, using the crystal’s electron density and symmetry, the software is able to ascertain the location of all atoms throughout the entire protein structure in the form of a protein model. The software next refines the protein model and improves the electron density map in order to provide a comprehensive view of the protein, which can then be displayed in the form of a 3-D model.

While the HKL family of software can be used to map a vast range of macromolecules and smaller compounds, Minor’s lab focuses on those proteins related to human health and disease in hopes of developing more concrete knowledge of the structure-function relationship. For example, by mapping the protein structures related to allergies, Parkinson’s disease and even cancer, Minor’s team ultimately seeks to be able to more effectively combat these diseases with targeted drug treatments.

According to Minor, who emigrated from Warsaw, Poland, in 1985, the key to success as an inventor is to always keep an eye to the future. “With new discoveries come different research problems,” he says. “When I approach my research, I focus on the next five to 10 years. Forget now — what will our problems be 10 years down the road?”