The calculated free energies correlate with experimentally measured IC50 values and comparably ponatinib has better binding towards the mutation T315A than T315I. The free energy of BCR-ABLT315I Life Science Reagents complexed with imatinib is 29.89 kcal/mol indicating that ponatinib has higher binding towards T315I mutation compared to imatinib. Table 1 shows the distribution of electrostatic potential and contribution from neighbouring residues during MD simulations that are responsible for this free energy change. The Y253F mutation has 2 fold greater activity than Y253H, although the net SIE values for both complexes do not correlate with observed experimental values. These mutations show decrease in intermolecular coulomb energies compared to native kinase and Y253F mutation shows decreased vdW interaction energies. Phe317 located at middle of the hinge region is in ATP binding site, imidazo pyridazine ring of ponatinib interacts with Phe317 via pi-pi stacking and vdW contacts. From the analysis of MD simulations of F317V BCR-ABL kinase – ponatinib complex, we observed slightly increased intermolecular vdW energy and cavity value and decreased intermolecular coulomb value. The SIE free energy for F317V BCR-ABL kinase �C ponatinib complex is which is close to the SIE free energy of F317L. The residue Phe359 is located on turn region at the end of aChelix and is involved in the formation of a hydrophobic core with several residues from aC- helix including hydrophobic amino acids Val289 and Ile293. The F359V is adjacent to piperazine solubilization group of ponatinib and forms weak vdW interactions. The SIE binding free energy was observed for this complex. In spite of side chains being oriented away from the binding site of ponatinib, the P-loop mutations E255K and E255V are closer to ponatinib effecting its activity. The structure Enzalutamide superposition of ponatinib and imatinib is shown in Figure 4 and both inhibitors bind BCR-ABL kinase at exactly the same location. Further despite the peptide bond swap, both inhibitors vary only in two locations. 1. The presence of CF3 group on piperazine substituted phenyl ring. 2. The presence of acetylene linked imidazo pyridazine ring. The CF3 group makes close contacts with hydrophobic side chains of Leu298 and Leu354. From Table 2, we observed that Leu298 has stable interactions with CF3 throughout MD simulations in all mutations, while Leu354 experiences increased vdW interactions with mutations E255K and T315A. Thr315 is close to acetylene link of ponatinib and imidazo pyridazine ring is in a hydrophobic cavity that is enclosed by Leu248, Tyr253, Phe382, Phe317 and Leu370. Among these, Leu370 makes stable CH-pi interactions with imidazo pyridazine ring contributing to the stability of native and mutant complexes. The other four residues in most BCR-ABL kinase mutants when bound to ponatinib undergo high conformational changes during MD simulations. We believe that these conformational changes are responsible for ponatinib binding and inhibition of native and mutant BCR-ABL kinases. The pan-BCR-ABL kinase inhibitor, ponatinib is most popular for its inhibition of ABLT315I mutation at nano molar concentrations. Fourteen mutant ABL kinase structures complexed with ponatinib were modeled and we performed 25 ns of MD simulations to study the structural changes of protein when complexed with ponatinib within its binding site. Using the SIE method, we calculated binding free energies and its component of non bonding energies such as intermolecular vdW energies and reaction field energies. Further, coulomb and vdW contributions from individual amino acid residues in active site were calculated. The calculated SIE values are in the range 210.03 kcal/mol to 210.67 kcal/mol and correspond with the narrow range of IC50 values of native and mutant BCR-ABL kinase inhibition by ponatinib. From these MD simulations, we observed that fluctuations in residues from P-loop, b3-, b5- strands and aC- helix are mainly responsible for ponatinib binding to native and all mutant BCR-ABL kinases. Further, amino acid residues Met244, Lys245, Gln252, Gly254, Leu370 and Leu298 did not undergo any conformational changes due to mutations. The rest of the mutations effect ponatinib binding free energy calculations with its component energies evidently correlating with their activities.