The Conformational Transition Pathways and Hidden Intermediates in DFG-Flip Process of c‑Met Kinase Revealed by Metadynamics Simulations
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The cover article of JCIM in the July 2022 issue showed the results of a collaborative project between Divamics, Wuhan University of Technology, and Institute of Precision Measurement, Chinese Academy of Sciences.  In this work, the meta-dynamics approach was used to analyze the flexibility mechanism of c-Met target proteins, which play important roles in RAS, PI3K, STAT and other pathways.

The paper, co-authored by Tao Jiang, Zhenhao Liu, Wenlang Liu, Jiawen Chen, Zheng Zheng, and Mojie Duan, investigated the structural transition of the DFG domain of c-Met kinase and found two transition pathways, one of which, pathway II, has not been reported in previous research. One of them, pathway II, has not been reported in the previous research work. The intermediate state in the newly discovered pathway can be used as a special structural conformation of the receptor for the development of highly selective drugs against c-Met kinase using computer-aided drug design methods. In addition, the combination of traditional molecular dynamics and meta-dynamics-enhanced sampling methods can also be applied to other kinases to explore the hidden transition mechanism.

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J. Chem. Inf. Model. 2022, 62, 3651−3663