In a new NSF-funded collaboration, the Voelz Lab is working with the Roder Lab at Fox Chase Cancer Center to study early folding events in apomyoglobin.
Apomyoglobin (myoglobin without the heme group) is an extremely well-studied protein. In fact, mygolobin was the first protein to have its structure solved by x-ray crystallography (John Kendrew, 1958). At low pH, apomyoglobin assumes a “molten globule” state that is compact and only partially structured. Seminal experiments by Jennings and Wright (1993) showed that when apomyoglobin folds at normal pH, it goes through an early intermediate that closely corresponds to the low-pH molten globule state.
Now, more recent experiments from the Roder lab have revealed even more details of early folding events in myoglobin (Xu et al. 2012). Using Trp fluorescence spectroscopy in a continuous-flow fast mixer, the Roder lab have resolved the formation of up to four different conformational states, on timescales ranging from microseconds to milliseconds.
The Voelz Lab is working toward using molecular simulation to characterize these conformational states in atomic detail. Both the size of the protein (153 residues) and the timescale of early folding (~200 µs) make this a challenging problem to tackle, but we hope that simulations on Folding@home (coming soon!) combined with Markov State Model approaches will enable us to construct a highly detailed model of the early folding reaction, and new level of quantitative connection between simulations and experiments. In the years to come, this work will lead to new ways to combine computation and experiment to understand and fight human diseases.