Protein Puzzle Falls into Place
By Jade Boyd
When one of the founders of a field says you’ve made a major breakthrough, you can pretty well bet you’ve found something important.
The breakthrough in this case is a new way to analyze the moving parts of large proteins, which will make it easier for structural biologists to classify and scrutinize the active sites of proteins implicated in cancer and other diseases. The researchers used a mathematical algorithm to narrow down all the possible ways a protein might flex and bend in conjunction with information captured via X-ray crystallography, a technique in which protein crystals are bombarded with X-rays, to reveal the precise three-dimensional arrangement of every atom in the protein.
The interinstitutional research involved scientists from Baylor College of Medicine and Rice, led by Jianpeng Ma, who holds joint appointments at both institutions. “Increasingly,” Ma said, “our discipline is faced with deciphering the structure of large, complex proteins in which some parts are constantly moving, even when the protein is locked in a crystal form.”
According to Harvard University’s William Lipscomb, a Nobel laureate who co-founded protein crystallography, “This success is revolutionary for the field of structure biology and is one of the largest technical leaps forward in X-ray refinement in the last two decades. It will fundamentally change the way people do structural refinement for large and flexible complexes.”
A protein is a chain of amino acids strung end-to-end, and Ma said current techniques are good at deciphering all but the most flexible parts of proteins. However, the most flexible parts often are those most vital to the protein’s function — such as the site where an enzyme catalyzes a reaction or where a signaling protein docks with its partners.
“When proteins move, they do it for a reason,” said Ma. “It is perhaps ironic that current techniques give us the fuzziest detail in the regions where we desire the most clarity.”
“This success is revolutionary for the field of structure biology and is one of the largest technical leaps forwards in X-ray refinement in the last two decades. It will fundamentally change the way people do structural refinement for large and flexible complexes.”Ma first imagined developing a new mathematical algorithm to zero in on these mobile sites about a decade ago, and after four years of working the problem himself, with very little progress, he assigned it to Rice graduate student Billy Poon in mid-2001. “The success of this project,” Ma said, “is really a story about Billy’s perseverance and determination.”- William Lipscomb, Harvard University
Poon never lost faith in the basic premise of the project, although producing results took some time. “All indications were that it should work,” he said. “I did start to get worried in the fourth and fifth years because I needed to finish.”
The project’s pieces started to fall into place last fall, but a huge hurdle remained: The protein Ma and Poon were using as a test case had to be “fitted” to the map that Poon’s program had produced. This final step was like an enormous puzzle, and to solve it, students put on special goggles that allowed them to see computerized 3-D representations of both the map and the protein. They would then fit the parts of the protein within the mapped area, although in doing so, they often inadvertently moved a different part of the protein out of alignment elsewhere. The problem was magnified by the fact that only a small fraction of the entire puzzle was visible on the screen at one time.
The task of fitting the protein fell to BCM student Xiaorui Chen, who joined Ma’s group as part of her medical school rotation. Protein fitting is an art for which Chen has an enormous talent, Ma said, in part because she has studied proteins since high school.
When the problem finally was solved, Poon was overjoyed at being able to publish the results of his long years of study. “If anything, I was even happier,” Ma said. “Nobody was sure it would work out before that, and it’s a rare treat when a scientist gets to witness a success like this one.”
Other co-authors of the paper were BCM faculty members Florante Quiocho and Qinghua Wang. Poon was supported by the Houston Area Molecular Biophysics Predoctoral Training Program. Other funding agencies that contributed to the work were the National Institutes of Health, the National Science Foundation and the Welch Foundation, as well as Hewlett Packard and Intel via their support of the Rice Terascale Cluster. The research appeared in the Proceedings of the National Academy of Science.