The dynamic conformational landscapes of the protein methyltransferase SETD8


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+.
Submitted. [bioRxiv] 
* 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.

A water-mediated allosteric network governs activation of Aurora kinase A

Cyphers S, Ruff E, Behr JM, Chodera JD, and Levinson NM.
Nature Chemical Biology 13:402, 2017. [DOI] [PDF] [GitHub]

Over 50 microseconds of aggregate simulation data on Folding@home reveal a surprisingly stable hydrogen bond network underlies allosteric activation by Tpx2.

Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Xu Jianing, Pham CG, Albanese SK, Dong Yiyu, Oyama T, Lee CH, Rodrik-Outmezguine V, Yao Z, Han S, Chen D, Parton DL, Chodera JD, Rosen N, Cheng EH, and Hsieh J. Journal of Clinical Investigation 126:3526, 2016. [DOI] [PDF]

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