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Towards simple kinetic models of functional dynamics for a kinase subfamily

Nature Chemistry volume 10, pages 903–909 (2018)Cite this article

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Abstract

Kinases are ubiquitous enzymes involved in the regulation of critical cellular pathways. However, in silico modelling of the conformational ensembles of these enzymes is difficult due to inherent limitations and the cost of computational approaches. Recent algorithmic advances combined with homology modelling and parallel simulations have enabled researchers to address this computational sampling bottleneck. Here, we present the results of molecular dynamics studies for seven Src family kinase (SFK) members: Fyn, Lyn, Lck, Hck, Fgr, Yes and Blk. We present a sequence invariant extension to Markov state models, which allows us to quantitatively compare the structural ensembles of the seven kinases. Our findings indicate that in the absence of their regulatory partners, SFK members have similar in silico dynamics with active state populations ranging from 4 to 40% and activation timescales in the hundreds of microseconds. Furthermore, we observe several potentially druggable intermediate states, including a pocket next to the adenosine triphosphate binding site that could potentially be targeted via a small-molecule inhibitor.

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Fig. 1: Starting structures for the Fyn simulations were generated from a Src-based homology model that corresponds to the inactive state and from a crystal structure of Fyn in its active state22.
Fig. 2: ATP-bound Fyn samples a kinome-wide ‘DFG in’ conformational landscape.
Fig. 3: Activation is a concerted process: model for Fyn kinase starting from the Src-like inactive state and ending in the active state.
Fig. 4: Catalytic domains of SFK members sample several macrostates with active states being within 2 kcal mol−1 of the inactive state.

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Acknowledgements

The authors thank the donors of the Folding@home distributed computing platform for providing the computer power used for this project. M.M.S. acknowledges support from the National Science Foundation (grant NSF-MCB-0954714) and the National Institutes of Health (S10 Shared Instrumentation grant 1S10RR02664701) for their support of the Biox3 computer cluster at Stanford. G.K. acknowledges support from the the NIH Simbios Program, and the Center for Molecular Analysis and Design at Stanford. The authors also thank D. Shukla, M. Harrigan, B. Husic, A. Peck, J. Shi, C. Hernández and other members of the Pande Lab for many insightful discussions and critical comments on the manuscript.

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  1. Gert Kiss

    Present address: Revolution Medicines, Redwood City, CA, USA

Authors and Affiliations

  1. Department of Chemistry, Stanford University, Stanford, CA, USA

    Mohammad M. Sultan & Gert Kiss

  2. Center for Molecular Analysis and Design, Stanford University, Stanford, CA, USA

    Gert Kiss

  3. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Vijay S. Pande

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Contributions

M.M.S., G.K. and V.S.P. designed the study. M.M.S. ran and analysed the simulations. M.M.S. and G.K. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Vijay S. Pande.

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M.M.S. declares no competing interests. G.K. is currently employed by Revolution Medicines. V.S.P. is a consultant and Scientific Advisory Board (SAB) member of Schrodinger LLC and Globavir, sits on the Board of Directors of Apeel Inc., Freenome Inc., Omada Health, Patient Ping and Rigetti Computing, and is a General Partner at Andreessen Horowitz.

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Sultan, M.M., Kiss, G. & Pande, V.S. Towards simple kinetic models of functional dynamics for a kinase subfamily. Nature Chem 10, 903–909 (2018). https://doi.org/10.1038/s41557-018-0077-9

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