@article{TEXTUAL,
      recid = {13412},
      author = {Peng, Xiangda and Baxa, Michael and Faruk, Nabil and  Sachleben, Joseph R. and Pintscher, Sebastian and Gagnon,  Isabelle A. and Houliston, Scott and Arrowsmith, Cheryl H.  and Freed, Karl F. and Rocklin, Gabriel J. and Sosnick,  Tobin R.},
      title = {Prediction and Validation of a Protein’s Free Energy  Surface Using Hydrogen Exchange and (Importantly) Its  Denaturant Dependence},
      journal = {Journal of Chemical Theory and Computation},
      address = {2021-12-22},
      number = {TEXTUAL},
      abstract = {The denaturant dependence of hydrogen–deuterium exchange  (HDX) is a powerful measurement to identify the breaking of  individual H-bonds and map the free energy surface (FES) of  a protein including the very rare states. Molecular  dynamics (MD) can identify each partial unfolding event  with atomic-level resolution. Hence, their combination  provides a great opportunity to test the accuracy of  simulations and to verify the interpretation of HDX data.  For this comparison, we use Upside, our new and extremely  fast MD package that is capable of folding proteins with an  accuracy comparable to that of all-atom methods. The FESs  of two naturally occurring and two designed proteins are so  generated and compared to our NMR/HDX data. We find that  Upside’s accuracy is considerably improved upon modifying  the energy function using a new machine-learning procedure  that trains for proper protein behavior including realistic  denatured states in addition to stable native states. The  resulting increase in cooperativity is critical for  replicating the HDX data and protein stability, indicating  that we have properly encoded the underlying physiochemical  interactions into an MD package. We did observe some  mismatch, however, underscoring the ongoing challenges  faced by simulations in calculating accurate FESs.  Nevertheless, our ensembles can identify the properties of  the fluctuations that lead to HDX, whether they be small-,  medium-, or large-scale openings, and can speak to the  breadth of the native ensemble that has been a matter of  debate.},
      url = {http://knowledge.uchicago.edu/record/13412},
}