Rafal P. Wiewiora*, Shi Chen*, Fanwang Meng, Nicolas Babault, Anqi Ma, Wenyu Yu, Kun Qian, Hao Hu, Hua Zou, Junyi Wang, Shijie Fan, Gil Blum, Fabio Pittella-Silva, Kyle A. Beauchamp, Wolfram Tempel, Hualing Jiang, Kaixian Chen, Robert Skene, Y. George Zheng, Peter J. Brown, Jian Jin, John D. Chodera+, and Minkui Luo+.
* These authors contributed equally to this work
+ Co-corresponding authors
In this work, we show how targeted X-ray crystallography using covalent inhibitors and depletion of native ligands to reveal structures of low-population hidden conformations can be combined with massively distributed molecular simulation to resolve the functional dynamic landscape of the protein methyltransferase SETD8 in unprecedented atomistic detail. Using an aggregate of six milliseconds of fully atomistic simulation from Folding@home, we use Markov state models to illuminate the conformational dynamics of this important epigenetic protein.