Conformational flexibility,binding energy,role of salt bridge and alanine-mutagenesis for c-Abl kinase complex |
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Authors: | Kshatresh Dutta Dubey Rajendra Prasad Ojha |
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Institution: | (1) Biophysics Unit, Department of Physics, DDU Gorakhpur University, Gorakhpur, 273 009, India |
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Abstract: | Abl kinase plays a decisive role in the mechanism of the most fatal human pathogen chronic mylogenous leukemia (CML). Here,
we have carried out a comprehensive study about the conformational flexibility, role of salt bridge and the protein- ligand
interaction for this kinase with its well-known inhibitor, Imatinib. We have performed molecular dynamics simulations for
conformational behavior, investigated the salt bridges and calculated the binding free energy of Imatinib with MM-PB/SA method
for Abl kinase complex. We also explored the role of salt-bridge in the kinase complex and its effect on binding activity
of inhibitors. Furthermore, to investigate the importance of those residues which form salt bridges, we mutated them by Alanine
with the help of Alanine scanning program. We noticed significant variations in total free energy of Imatinib in all possible
mutations. The binding free energy of ligand for kinase receptor was analyzed by molecular mechanics Poission Boltzmann surface
area (MM-PB/SA) method. These results suggest that conserved glutamic acid and lysine are necessary for stability of complex. |
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