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International Conference on Simulation and Modeling Methodologies, Technologies and Applications

SIMULTECH 2016: Simulation and Modeling Methodologies, Technologies and Applications pp 75–82Cite as

Proteins Flexibility as a Criterion for Elucidation of Activating Mutants in Personalized Cancer Medicine

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Part of the book series: Advances in Intelligent Systems and Computing ((AISC,volume 676))

Abstract

We developed a new strategy for elucidation of functional impact of mutations in proteins. Using molecular dynamics simulations, we explore flexibility of proteins in the sites of their binding to the other proteins. Binding of two or more proteins go through the stage of intermediate binding complexes. On this stage the number of possible conformations of the proteins’ binding sites are interacting with each other. Increasing flexibility in the binding sites increase a probability of the best-energy docking of proteins. Our computational simulations demonstrated that a missense alteration of MET (p.Tyr501Cys), which lead to an increase of flexibility of the protein, may improve the binding of the receptor with its ligand HGF (hepatocyte growth factor) and thus be considered as activating. Accordingly to this conclusion, a patient presenting a hepatocellular carcinoma MET Y501C-mutated showed a good response when treated by a potent MET inhibitor (cabozantinib), with a decrease of −65% of the alpha-foeto-protein (AFP).

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Author information

Authors and Affiliations

  1. Moores Cancer Center, University of California, San Diego, La Jolla, San Diego, CA, USA

    Igor F. Tsigelny, Razelle Kurzrock, Valentina L. Kouznetsova, Amélie Boichard & Sadakatsu Ikeda

  2. San Diego Supercomputer Center, University of California, San Diego, La Jolla, San Diego, CA, USA

    Igor F. Tsigelny, Åge Aleksander Skjevik & Valentina L. Kouznetsova

  3. Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA

    Igor F. Tsigelny

  4. Department of Biomedicine, University of Bergen, Bergen, Norway

    Åge Aleksander Skjevik

  5. CureMatch Inc., San Diego, CA, USA

    Igor F. Tsigelny

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  1. Igor F. Tsigelny
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  2. Razelle Kurzrock
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  4. Valentina L. Kouznetsova
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Correspondence to Igor F. Tsigelny .

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Editors and Affiliations

  1. King Abdullah II School of Information Technology, The University of Jordan, Amman, Jordan

    Mohammad S. Obaidat

  2. School of Electrical Engineering and Computer Science, University of Ottawa, Ottawa, Ontario, Canada

    Tuncer Ören

  3. Department of Modelling and Simulation, Riga Technical University, Riga, Latvia

    Yuri Merkuryev

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Tsigelny, I.F., Kurzrock, R., Skjevik, Å.A., Kouznetsova, V.L., Boichard, A., Ikeda, S. (2018). Proteins Flexibility as a Criterion for Elucidation of Activating Mutants in Personalized Cancer Medicine. In: Obaidat, M., Ören, T., Merkuryev, Y. (eds) Simulation and Modeling Methodologies, Technologies and Applications. SIMULTECH 2016. Advances in Intelligent Systems and Computing, vol 676. Springer, Cham. https://doi.org/10.1007/978-3-319-69832-8_5

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  • DOI: https://doi.org/10.1007/978-3-319-69832-8_5

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