Residue-specific free energy analysis in ligand bindings to JAK2

ABSTRACT

Janus kinase 2 (JAK2) has vital importance on the regulation of proliferation, survival and differentiation of a variety of cells by the activation of JAK-STAT pathway. In this study, we employ a new approach to quantitatively calculate residue-specific binding free energies to identify hot-spots in ligand bindings to JAK2 using computational alanine scanning technique combined with the interaction entropy method for entropic change in binding free energies. This combined approach allows one to quantitatively analyse important protein–ligand binding interactions, and in addition, provides a new method for more accurate computation of total protein–ligand binding free energy. In this report, we computed a total of 14 JAK2–ligand binding systems, all with crystal structures and experimentally measured binding data. Key residues are identified with L983 being the quantitatively dominant residue in binding free energy contributions to the ligands. The values of the computed total JAK2–ligand binding free energies are in much closer agreement with experimentally measured data than those obtained by using the standard MM/GBSA approach. Our study thus provided new insights into specific binding mechanisms in ligand binding to JAK2.

GRAPHICAL ABSTRACT

KEYWORDS:

• Residue-specific
• binding free energy
• interaction entropy
• JAK2
• MM/GBSA
• MD simulation
• alanine scanning

Acknowledgments

This work was supported by National Key R&D Program of China (grant no. 2016YFA0501700), National Natural Science Foundation of China (grant nos. 21433004, 91753103), Shanghai Putuo District (grant no. 2014-A-02), Innovation Program of Shanghai Municipal Education Commission (201701070005E00020), and NYU Global Seed Grant. We thank the Supercomputer Center of East China Normal University for providing us computer time.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

National Key R&D Program of China [grant number 2016YFA0501700]; National Natural Science Foundation of China [grant number 21433004], [grant number 91753103]; Shanghai Putuo District [grant number 2014-A-02]; Innovation Program of Shanghai Municipal Education Commission [201701070005E00020]; and NYU Global Seed Grant.