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Co-operative intra-protein structural response due to protein–protein complexation revealed through thermodynamic quantification: study of MDM2-p53 binding

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Abstract

The p53 protein activation protects the organism from propagation of cells with damaged DNA having oncogenic mutations. In normal cells, activity of p53 is controlled by interaction with MDM2. The well understood p53-MDM2 interaction facilitates design of ligands that could potentially disrupt or prevent the complexation owing to its emergence as an important objective for cancer therapy. However, thermodynamic quantification of the p53-peptide induced structural changes of the MDM2-protein remains an area to be explored. This study attempts to understand the conformational free energy and entropy costs due to this complex formation from the histograms of dihedral angles generated from molecular dynamics simulations. Residue-specific quantification illustrates that, hydrophobic residues of the protein contribute maximum to the conformational thermodynamic changes. Thermodynamic quantification of structural changes of the protein unfold the fact that, p53 binding provides a source of inter-element cooperativity among the protein secondary structural elements, where the highest affected structural elements (α2 and α4) found at the binding site of the protein affects faraway structural elements (β1 and Loop1) of the protein. The communication perhaps involves water mediated hydrogen bonded network formation. Further, we infer that in inhibitory F19A mutation of P53, though Phe19 is important in the recognition process, it has less prominent contribution in the stability of the complex. Collectively, this study provides vivid microscopic understanding of the interaction within the protein complex along with exploring mutation sites, which will contribute further to engineer the protein function and binding affinity.

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Acknowledgements

S.S. thanks the National Research Foundation of Singapore for support through BioSym Interdisciplinary Research group at Singapore-MIT Alliance for Research and Technology center.

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Authors and Affiliations

  1. BioSystems and Micromechanics IRG (BioSyM), Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Singapore, 138602, Singapore

    Sudipta Samanta

  2. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Sudipta Samanta

  3. Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Kolkata, West Bengal, 741246, India

    Sanchita Mukherjee

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  1. Sudipta Samanta
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Correspondence to Sudipta Samanta.

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Samanta, S., Mukherjee, S. Co-operative intra-protein structural response due to protein–protein complexation revealed through thermodynamic quantification: study of MDM2-p53 binding. J Comput Aided Mol Des 31, 891–903 (2017). https://doi.org/10.1007/s10822-017-0057-y

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