DNA provides the blueprint for life, but proteins are the molecules that make life happen. Since many diseases arise from dysfunctional protein activity, a detailed understanding into how proteins function is crucial to develop effective, molecular-based therapies for treating disease.
It has been said that “a picture is worth a thousand words.” Our lab has developed experimental methods that make it possible to take near-atomic resolution snapshots of a protein’s structure with an exposure time as short as 0.1 billionth of a second. We are concurrently working to reduce our exposure time down to less than 1 trillionth of a second. Why so fast? Because the functional protein motions we seek to characterize can occur on ultrafast time scales, they will be smeared out if our exposure time is too long. By stitching together individual snapshots into movies, we can literally watch a protein as it functions, and read chapter one of a protein’s story.
We use ultrafast time-resolved laser spectroscopy and x-ray diffraction to study proteins as they perform their targeted function. These experimental techniques employ the pump-probe method in which a laser pump pulse triggers a structural change in a protein, and a suitably delayed probe pulse records the protein’s absorption spectrum (spectroscopy), or its stucture (x-ray diffraction). By changing the time delay between the pump and probe pulses, we can track time-dependent changes in the protein structure and examine how those changes influence its function. By watching a protein as it functions in real time, we aim to generate a detailed understanding into how it functions, and thereby unveil the biophysical equivalent of pistons, levers, wheels, and gears in Nature’s remarkable nanoscale molecular machines. This knowledge will help us better understand the conditions under which a protein might suffer dysfunction, and provide a molecular basis for treating disease.