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Conformational flexibility, binding energy, role of salt bridge and alanine-mutagenesis for c-Abl kinase complex

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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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Acknowledgments

The partial computational work is carried out at Supercomputing facility for bioinformatics and computational biology, Indian Institute of Technology, New Delhi, India, their support is gratefully acknowledged. Special thanks to Prof. B. Jayaram, coordinator SCFbio, Indian Institute of Technology, New Delhi (IITD) to facilitate the access of supercomputer at IITD. Authors are grateful to Dr. Azara Praveen, Zakir Hussain College of Engineering and Technology, Aligarh Muslim University, Aligarh, for proofing the manuscript. KDD thanks to Council for Scientific and Industrial Research (CSIR) for the award of senior research fellowship.

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  1. Biophysics Unit, Department of Physics, DDU Gorakhpur University, Gorakhpur, 273 009, India

    Kshatresh Dutta Dubey & Rajendra Prasad Ojha

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  1. Kshatresh Dutta Dubey
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  2. Rajendra Prasad Ojha
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Correspondence to Kshatresh Dutta Dubey or Rajendra Prasad Ojha.

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Dubey, K.D., Ojha, R.P. Conformational flexibility, binding energy, role of salt bridge and alanine-mutagenesis for c-Abl kinase complex. J Mol Model 18, 1679–1689 (2012). https://doi.org/10.1007/s00894-011-1199-9

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  • DOI: https://doi.org/10.1007/s00894-011-1199-9

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