Dataset Information

Identification of Druggable Kinase Target Conformations Using Markov Model Metastable States Analysis of apo-Abl.

ABSTRACT: Kinases are important targets for drug development. However, accounting for the impact of possible structural rearrangements on the binding of kinase inhibitors is complicated by the extensive flexibility of their catalytic domain. The dynamic N-lobe contains four particular mobile structural elements: the Asp-Phe-Gly (DFG) motif, the phosphate (P) positioning loop, the activation (A) loop, and the ?C helix. In our previous study [Meng et al. J. Chem. Theory Comput. 2018 14, 2721-2732], we combined various simulation techniques with Markov state modeling (MSM) to explore the free energy landscape of Abl kinase beyond conformations that are known from X-ray crystallography. Here we examine the resulting Markov model in greater detail by analyzing its metastable states. A characterization of the states in terms of their DFG state, P-loop, and ?C conformations is presented and compared to existing classification schemes. Several metastable states are found to be structurally close to known crystal structures of different kinases in complex with a variety of inhibitors. These results suggest that the set of conformations accessible to tyrosine kinases may be shared within the entire family and that the conformational dynamics of one kinase in the absence of any ligand can provide meaningful information about possible target conformations for inhibitors of any member of the kinase family.

SUBMITTER: Paul F

PROVIDER: S-EPMC7398592 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification of Druggable Kinase Target Conformations Using Markov Model Metastable States Analysis of apo-Abl.

Paul Fabian F Meng Yilin Y Roux Benoît B

Journal of chemical theory and computation 20200213 3

Kinases are important targets for drug development. However, accounting for the impact of possible structural rearrangements on the binding of kinase inhibitors is complicated by the extensive flexibility of their catalytic domain. The dynamic N-lobe contains four particular mobile structural elements: the Asp-Phe-Gly (DFG) motif, the phosphate (P) positioning loop, the activation (A) loop, and the αC helix. In our previous study [Meng et al. <i>J. Chem. Theory Comput.</i> 2018 14, 2721-2732], w ...[more]

PMID: 31999924

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Project description:BackgroundKinases are a family of enzymes that catalyze the transfer of the ɤ-phosphate group from ATP to a protein's residue. Malfunctioning kinases are involved in many health problems such as cardiovascular diseases, diabetes, and cancer. Kinases transitions between multiple conformations of inactive to active forms attracted considerable interest.MethodA reaction coordinate is computed for the transition between the active to inactive conformation in Abl kinase with a focus on the DFG-in to DFG-out flip. The method of Rock Climbing is used to construct a path locally, which is subsequently optimized using a functional of the entire path. The discrete coordinate sets along the reaction path are used in a Milestoning calculation of the free energy landscape and the rate of the transition.ResultsThe estimated transition times are between a few milliseconds and seconds, consistent with simulations of the kinetics and with indirect experimental data. The activation requires the transient dissociation of the salt bridge between Lys271 and Glu286. The salt bridge reforms once the DFG motif is stabilized by a locked conformation of Phe382. About ten residues are identified that contribute significantly to the process and are included as part of the reaction space.ConclusionsThe transition from DFG-in to DFG-out in Abl kinase was simulated using atomic resolution of a fully solvated protein yielding detailed description of the kinetics and the mechanism of the DFG flip. The results are consistent with other computational methods that simulate the kinetics and with some indirect experimental measurements.General significanceThe activation of kinases includes a conformational transition of the DFG motif that is important for enzyme activity but is not accessible to conventional Molecular Dynamics. We propose a detailed mechanism for the transition, at a timescale longer than conventional MD, using a combination of reaction path and Milestoning algorithms. The mechanism includes local structural adjustments near the binding site as well as collective interactions with more remote residues.

Dataset Information

Identification of Druggable Kinase Target Conformations Using Markov Model Metastable States Analysis of apo-Abl.

Publications

Identification of Druggable Kinase Target Conformations Using Markov Model Metastable States Analysis of apo-Abl.

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