Dataset Information

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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Publications

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]

PMID: 29474075

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Project description:Studies of resting state functional MRI (rs-fRMI) are increasingly focused on "dynamics", or on those properties of brain activation that manifest and vary on timescales shorter than the scan's full duration. This shift in focus has led to a flurry of interest in developing hypothesis testing frameworks and null models applicable to the dynamical setting. Thus far however, these efforts have been weakened by a number of crucial shortcomings that are outlined and discussed in this article. We focus here on aspects of recently proposed null models that, we argue, are poorly formulated relative to the hypotheses they are designed to test, i.e., their potential role in separating functionally relevant BOLD signal dynamics from noise or intermittent background and maintenance type processes is limited by factors that are fundamental rather than merely quantitative or parametric. In this short position paper, we emphasize that (1) serious care must be exercised in building null models for rs-fMRI dynamics from distributionally stationary univariate or multivariate timeseries, i.e., timeseries whose values are each independently drawn from one pre-specified probability distribution; and (2) measures such as kurtosis that quantify over-concentration of observed values in the far tails of some reference distribution may not be particularly suitable for capturing signal features most plausibly contributing to functionally relevant brain dynamics. Other metrics targeted, for example, at capturing the type of epochal signal variation that is often viewed as a signature of brain responsiveness to stimuli or experimental tasks, could play a more scientifically clarifying role. As we learn more about the phenomenon of functionally relevant brain dynamics and its imaging correlates, scientifically meaningful null hypotheses and well-tuned null models will naturally emerge. We also revisit the important concept of distributional stationarity, discuss how it manifests within realizations vs. across multiple realizations, and provide guidance on the benefits and limitations of employing this type of stationarity in modeling the absence of functionally relevant temporal dynamics in resting state fMRI. We hope that the discussions herein are useful, and promote thoughtful consideration of these important issues.

Dataset Information

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

Publications

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

Similar Datasets

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