Stephen D. Fried, Assistant Professor of Chemistry at Johns Hopkins University, Baltimore, MD, will give a talk titled, "How to Fold the Proteome: Mission Accomplished?"

This seminar will also be available by Zoom. Zoom link: https://gc-cuny.zoom.us/j/91448257859?pwd=2dSdb1Ne4u1liuzauChpsX5m6Ya5L…; Meeting ID: 914 4825 7859.  Passcode:  asrc+ccny

ABSTRACT

Recent advances in artificial intelligence have addressed a long-standing question in protein biophysics: What is the relationship between a protein’s primary sequence and its native three-dimensional structure? On the other hand, the process by which proteins navigate to these native states during their biosynthesis or following their denaturation is perilous, complex, and much less predictable. Many proteins misfold, a process which can sometimes be reverted (but not always) through chaperones, and is moreover associated with a wide range of ailments, particularly neurodegenerative diseases. My lab became interested in delineating which (kinds of) proteins are capable of refolding into their native conformations spontaneously versus which ones require chaperone assistance. To do so, we developed limited proteolysis mass spectrometry (LiP-MS) methods, a structural proteomic approach that can interrogate protein conformation and misfolding on the proteome scale. These experiments provide a holistic view of what properties facilitate refoldability and have highlighted an important and unexpected role for intrinsically disordered regions. In this talk, I want to emphasize that despite great strides in AI-based tools, there are still many surprises for this field. For instance, we have recently discovered a case of a protein whose misfolded form is even more kinetically stable than its native form. We also have documented a case of a protein whose folding is obstructed (rather than promoted) by the chaperone, Trigger Factor. Though it remains to be seen how widespread these "unusual" cases are, these results highlight the importance of us continuing to think deeply about protein folding with the spirit of curiosity and exploration, and showcases the power of emerging proteome-wide experimental approaches.