Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib

The kinase domain is highly conserved among protein kinases 'in terms of both sequence and structure. Conformational rearrangements of the kinase domain are affected by the phosphorylation of residues and the binding of kinase inhibitors. Interestingly, the conformational rearrangement of the active pocket plays an important role in kinase activity and can be used to design novel kinase inhibitors. We characterized the conformational plasticity of the active pocket when bosutinib was bound to salt-inducible kinase 2 (SIK2) using homology modeling and molecular dynamics simulations. Ten different initial complex models were constructed using the Morph server, ranging from open to closed conformations of SIK2 binding with bosutinib. Our simulation showed that bosutinib binds SIK2 with up or down conformations of the P-loop and with all the conformations of the activation loop. In addition, the aC-helix conformation was induced by the conformation of the activation loop, and the salt bridge formed only with its open conformation. The binding affinity of the models was also determined using the molecular mechanics generalized Born surface area method. Bosutinib was found to form a strong binding model with SIK2 and hydrophobic interactions were the dominant factor. This discovery may help guide the design of novel SIK2 inhibitors. (c) 2022 Sichuan University. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).