Theoretical Calculation And Prediction Of The Residue-specific Interaction Between JAK2

Janus kinase 2(JAK2)is a key member of Janus kinase family and has vital importance on the regulation of proliferation,survival and differentiation of a variety of cells by the activation of JAK-STAT3/STAT5 pathway.Since the V617 F mutant of JAK2 is associated with the pathogenesis of various myeloid diseases,it is critical to discovery inhibitors against the mutant protein for relief the patients from related diseases.In this thesis,we made use of a new approach Alanine Scanning-Interaction Entropy(AS-IE)to obtain quantitative contributions of individual residues in protein-ligand complexes.Hot-spot which is dominant residue in binding systems would be predicted and the total binding free energies of protein-ligand complexes were evaluated by using alanine-scanning method combined with the interaction entropy technique that calculates entropic change in binding free energies.Based on hot-spots,the existing small molecule inhibitors can be optimized and new binding compounds can be designed for inhibiting the abnormal JAK2 protein.We quantitatively analyzed a total of 14 JAK2-ligand complexes which have crystal structure and experimentally measured affinity data for evaluate on of residue-specific binding free energies and the corresponding total protein-ligand binding free energy.The computational results of JAK2-ligand binding free energies obtained by AS-IE are in much better agreement with experimental affinity data than those calculated using the MM/GBSA approach.Our new method provided new insights for residue-specific binding energy and total binding free energies of JAK2-ligand complexes.Based on the accuracy of AS-IE in JAK2 protein-ligand binding energy prediction,we screened the small molecule database SPECS for JAK2,and the docked JAK2-ligand complexes was analyzed with AS-IE to evaluate the hot-spots and corresponding binding free energy which can provide reference for future research of JAK2 inhibitors.