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Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models.


ABSTRACT: Understanding protein conformational variability remains a challenge in drug discovery. The issue arises in protein kinases, whose multiple conformational states can affect the binding of small-molecule inhibitors. To overcome this challenge, we propose a comprehensive computational framework based on Markov state models (MSMs). Our framework integrates the information from explicit-solvent molecular dynamics simulations to accurately rank-order the accessible conformational variants of a target protein. We tested the methodology using Abl kinase with a reference and blind-test set. Only half of the Abl conformational variants discovered by our approach are present in the disclosed X-ray structures. The approach successfully identified a protein conformational state not previously observed in public structures but evident in a retrospective analysis of Lilly in-house structures: the X-ray structure of Abl with WHI-P154. Using a MSM-derived model, the free energy landscape and kinetic profile of Abl was analyzed in detail highlighting opportunities for targeting the unique metastable states.

SUBMITTER: Meng Y 

PROVIDER: S-EPMC6317529 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models.

Meng Yilin Y   Gao Cen C   Clawson David K DK   Atwell Shane S   Russell Marijane M   Vieth Michal M   Roux Benoît B  

Journal of chemical theory and computation 20180403 5


Understanding protein conformational variability remains a challenge in drug discovery. The issue arises in protein kinases, whose multiple conformational states can affect the binding of small-molecule inhibitors. To overcome this challenge, we propose a comprehensive computational framework based on Markov state models (MSMs). Our framework integrates the information from explicit-solvent molecular dynamics simulations to accurately rank-order the accessible conformational variants of a target  ...[more]

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