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Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated molecular dynamics simulations: a dynamic odyssey

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Abstract

The Janus kinases (JAK) are crucial targets in drug development for several diseases. However, accounting for the impact of possible structural rearrangements on the binding of different kinase inhibitors is complicated by the extensive conformational variability of their catalytic kinase domain (KD). The dynamic KD contains mainly four prominent mobile structural motifs: the phosphate-binding loop (P-loop), the αC-helix within the N-lobe, the Asp-Phe-Gly (DFG) motif, and the activation loop (A-loop) within the C-lobe. These distinct structural orientations imply a complex signal transmission path for regulating the A-loop’s flexibility and conformational preference for optimal JAK function. Nevertheless, the precise dynamical features of the JAK induced by different types of inhibitors still remain elusive. We performed comparative, microsecond-long, Gaussian accelerated molecular dynamics simulations in triplicate of three phosphorylated JAK2 systems: the KD alone, type-I ATP-competitive inhibitor (CI) bound KD in the catalytically active DFG-in conformation, and the type-II inhibitor (AI) bound KD in the catalytically inactive DFG-out conformation. Our results indicate significant conformational variations observed in the A-loop and αC helix motions upon inhibitor binding. Our studies also reveal that the DFG-out inactive conformation is characterized by the closed A-loop rearrangement, open catalytic cleft of N and C-lobe, the outward movement of the αC helix, and open P-loop states. Moreover, the outward positioning of the αC helix impacts the hallmark salt bridge formation between Lys882 and Glu898 in an inactive conformation. Finally, we compared their ligand binding poses and free energy by the MM/PBSA approach. The free energy calculations suggested that the AI’s binding affinity is higher than CI against JAK2 due to an increased favorable contribution from the total non-polar interactions and the involvement of the αC helix. Overall, our study provides the structural and energetic insights crucial for developing more promising type I/II JAK2 inhibitors for treating JAK-related diseases.

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Data availability

The data that support the findings of this study are available from the corresponding author (PK) upon reasonable request.

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Acknowledgements

The Department of Science and Technology (DST), Govt. of India (grant number DST/NSM/R&D_HPC_Applications/2021/03.18). MFS would like to thank DST, Govt. of India, for providing a doctoral fellowship under the INSPIRE Fellowship Scheme (DST/INSPIRE Fellowship/2017/IF170145). SS thanks the Ministry of Education, Govt. of India, for providing a doctoral fellowship under the Prime Minister’s Research Fellows (PMRF) scheme. SP thanks the Ministry of Education, Govt. of India, for providing a doctoral fellowship under the JRF scheme.

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Author notes

  1. Md Fulbabu Sk

    Present address: Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology, NIH Resource for Macromolecular Modeling and Visualization, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA

  2. Md Fulbabu Sk and Sunanda Samanta have equally contributed to this work.

Authors and Affiliations

  1. Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, MP, 453552, India

    Md Fulbabu Sk, Sunanda Samanta, Sayan Poddar & Parimal Kar

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  1. Md Fulbabu Sk
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  2. Sunanda Samanta
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  3. Sayan Poddar
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  4. Parimal Kar
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Contributions

PK conceived and supervised the project. MFS, SS, and SP conducted molecular dynamics simulations and data analysis. MFS and SS wrote the manuscript. PK edited the manuscript. All authors have approved the final version of the manuscript.

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Correspondence to Parimal Kar.

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Tables: Hydrogen bond for R-spine, average network properties, free energy components, binding energy decomposed, hydrogen bonding for inhibitor and JAK2.

Figures: Backbone RMSD, probability distributions, the potential of mean force (PMF), PCA analysis plot, HRD motif dynamics, the time evolution of torsional angle, A-loop free energy landscape, distance probability distribution, salt-bridge interactions of active and inactive A-loop, RDF and SASA for phosphorylated residues, network properties differences, energy decomposition.

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Sk, M.F., Samanta, S., Poddar, S. et al. Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated molecular dynamics simulations: a dynamic odyssey. J Comput Aided Mol Des 38, 8 (2024). https://doi.org/10.1007/s10822-023-00548-8

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