Protein unfolding governed by geometric and steric principlesHoward J Feldman1, Christopher WV Hogue2
firstname.lastname@example.org, Samuel Lunenfeld Research Institute, Mount Sinai Hospital; email@example.com, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Using a novel physics-based approach the complete protein unfolding pathways for five distinct all-atom protein folds – barnase, alpha-lytic protease, lysozyme, chymotrypsin inhibitor 2 and the drkN SH3 domain – were computed and compared with recent results as computed and published using molecular dynamics and with in-vitro experiments. Although the effective computational step size taken is much larger than that used in molecular dynamics, the overall unfolding pathway and major unfolding events are similar, while the computation time is reduced by as much as three orders of magnitude. We are also able to identify likely folding initiation sites in our simulations which agree well with in-vitro experiment and molecular dynamics, and find that our simulations of drkN SH3 reproduce NOEs observed in the metastable unfolded exchange (Uexch) state. Our approach can be used to provide an accurate estimate of the important events of protein unfolding. That we are able to reproduce the molecular dynamics determined unfolding pathways of a number of different protein folds using this simplified model suggests that the unfolding pathways of small globular proteins are largely constrained by geometry and sterics.