6XJK

JAK2 JH2 in complex with JAK067

Summary for 6XJK

• Entry DOI: 10.2210/pdb6xjk/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 4-({4-amino-6-[(1H-indol-5-yl)oxy]-1,3,5-triazin-2-yl}amino)benzene-1-sulfonamide (3 entities in total)
• Functional Keywords: pseudokinase domain, inhibitor, complex, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33518.37

Authors

Puleo, D.E.,Krimmer, S.G.,Newton, A.S.,Schlessinger, J.,Jorgensen, W.L. (deposition date: 2020-06-24, release date: 2020-11-25, Last modification date: 2023-10-18)

Primary citation

Turupcu, A.,Tirado-Rives, J.,Jorgensen, W.L.
Explicit Representation of Cation-pi Interactions in Force Fields with 1/r4 Nonbonded Terms.
J Chem Theory Comput, 16:7184-7194, 2020

PubMed Abstract: The binding energies for cation-π complexation are underestimated by traditional fixed-charge force fields owing to their lack of explicit treatment of ion-induced dipole interactions. To address this deficiency, an explicit treatment of cation-π interactions has been introduced into the OPLS-AA force field. Following prior work with atomic cations, it is found that cation-π interactions can be handled efficiently by augmenting the usual 12-6 Lennard-Jones potentials with 1/ terms. Results are provided for prototypical complexes as well as protein-ligand systems of relevance for drug design. Alkali cation, ammonium, guanidinium, and tetramethylammonium were chosen for the representative cations, while benzene and six heteroaromatic molecules were used as the π systems. The required nonbonded parameters were fit to reproduce structure and interaction energies for gas-phase complexes from density functional theory (DFT) calculations at the ωB97X-D/6-311++G(d,p) level. The impact of the solvent was then examined by computing potentials of mean force (pmfs) in both aqueous and tetrahydrofuran (THF) solutions using the free-energy perturbation (FEP) theory. Further testing was carried out for two cases of strong and one case of weak cation-π interactions between druglike molecules and their protein hosts, namely, the JH2 domain of JAK2 kinase and macrophage migration inhibitory factor. FEP results reveal greater binding by 1.5-4.4 kcal/mol from the addition of the explicit cation-π contributions. Thus, in the absence of such treatment of cation-π interactions, errors for computed binding or inhibition constants of 10-10 are expected.

PubMed: 33048555
DOI: 10.1021/acs.jctc.0c00847

Experimental method

X-RAY DIFFRACTION (2.02350796538 Å)