I am investigating the kinetic barrier to unfolding in α-lytic protease (αLP). Using fluorescence and CD to measure the denaturant dependence of the activation free energy of unfolding, I have determined that the unfolding barrier is 26 kcal/mol. Taken together with refolding measurements, this indicates that the native state of aLP is actually less thermodynamically stable than both its unfolded and intermediate states (see figure, and Nature, 395: 817-819).
Thus, the αLP system provides a uniqure opportunity to dissect, both energetically and structurally, the components necessary for the extraordinary kinetic control responsible for maintenance of a thermodynamically unstable native fold, and to perhaps gain insight into the basis for large kinetic barriers in general.
I am currently determing the thermodynamic parameters of the unfolding barrier by monitoring the temperature dependence of unfolding, and I hope to use hydrogen exchange and NMR to discover partially folded intermediates which may transiently exist between the native and transition states. After graduating, I am interested in exploring the roles played by kinetic barriers, in addition to thermodynamic stability, in protein misfolding events that can lead to disease.

Unfolded conformations of α-lytic protease are more stable than its native state.
Julie L. Sohl*, Sheila S. Jaswal*, and David A. Agard, Nature 395, 817-819 (1998).
*These authors contributed equally to this work.

Thermodynamic parameters of the α-lytic protease unfolding transition state.
Sheila S. Jaswal and David A. Agard, manuscript in preparation.