Proteins at the Movies

When you open a biochemistry textbook, you'll see dozens of molecular structures frozen in the pages. These images have immensely advanced our understanding of proteins. Nevertheless, for most biological molecules, static poses give an incomplete, potentially misleading picture, because the molecules within our liquid innards are constantly changing shape.

These changes in shape, says Thomas James, a pharmaceutical chemist at the University of California at San Francisco, may drive certain chemical liaisons. A twisting, turning protein may bind only with another protein that recognizes similar shape-changing dynamics. In the case of environmental toxins, for instance, this insight may help researchers develop artificial proteins that trap them. And in the billion-dollar pharmaceutical industry, researchers always are striving to design drugs that bind selectively with proteins involved in disease processes.

"If we're going to put in this kind of effort," James says, "it would be nice to target a realistic picture of what the molecule is doing and what it looks like. My goal is that in a few years if I want to show you a molecule's structure, instead of a snapshot or slide, I'll show you a video."

The structure of this 13-basepair sequence of DNA from the HIV virus was determined by Thomas James and colleagues using NMR methods and computing at Pittsburgh Supercomputing Center. The spiral staircase-like double-helix structure forms from basepairs (red) that link the two DNA "backbones" (yellow).

Aligning DNA sequences from several HIV strains showed that this sequence, from the "long terminal repeat region" of the HIV-1 genome, is "highly conserved" -- i.e., it remains the same in different strains. This suggests that the sequence plays a role in HIV's ability to reproduce itself in human cells, and the structure is a potential target for antiviral drugs.


James is a leader in using nuclear magnetic resonance (NMR) methods to determine molecular structure. In recent work at the Pittsburgh Supercomputing Center, he has examined the dynamic structure of several proteins, including a regulatory protein that activates HIV, the virus that causes AIDS. James and his colleagues have also developed a promising new computational approach to the analysis of NMR structural data.

Researcher: Thomas James, University of California, San Francisco.
Hardware: CRAY C90
Software: AMBER, MARDIGRAS, CORMA, PARSE
Keywords: Biochemistry, molecular structure, protein, nuclear magnetic resonance (NMR), dynamic structure, static, virus, AIDS, motion, DNA, HIV, binding, viral transcription, PARSE, conformations, transactivation response (TAR), spatial orientation.

Related Material on the Web:
The James Group, Magnetic Resonance Laboratory.
The NMR Laboratory Home Page, from the University of California, San Francisco.
Projects in Scientific Computing, PSC's annual research report.

References, Acknowledgements & Credits