This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Downhill protein folding occurs when free energy barriers to folding are eliminated so that an entire ensemble of proteins can proceed along a single reaction co-ordinate. If a protein with only small local minima has its remaining barriers are quickly removed, intermediate structures can be distinctly and directly observed at each following timepoint without the need for single-molecule study. With sufficient time resolution, a series of these observations can be collected into a movie of protein conformational change that enables step-by-step comparisons against computational models used to predict protein folds from sequence. Downhill folding proteins have been discovered or engineered from several different folded structures, and high-power laser systems have been developed to provide sudden increases in temperature (""""""""T-jumps"""""""") which trigger folding from a cold-denatured state. Optical spectroscopy has been used to observe local structural changes in protein folding, but no methods are currently available for recording global protein shape with sufficient time resolution to catch the intermediate conformations during rapid downhill folding. Small Angle X-ray Scattering (SAXS) can provide low-spatial resolution structural information about proteins in solution;however the temporal resolution of existing approaches is far too slow to observe fast folding kinetics. We are developing a laser temperature-jump apparatus at the Advanced Photon Source Bio-CAT SAXS beamline to directly measure transient protein structures during fast folding processes.
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