Rational design of the survivin/CDK4 complex by combining protein-protein docking and molecular dynamics simulations

J Mol Model. 2013 Apr;19(4):1507-14. doi: 10.1007/s00894-012-1705-8. Epub 2012 Dec 21.

Abstract

Survivin, the smallest inhibitor of apoptosis protein (IAP), is a valid target for cancer research. It mediates both the apoptosis pathway and the cell cycle and has been proposed to form a complex with the cyclin-dependent kinase protein CDK4. The resulting complex transports CDK4 from the cytosol to the nucleus, where CDK4 participates in cell division. Survivin has been recognized as a node protein that interacts with several partners; disruption of the formed complexes can lead to new anticancer compounds. We propose a rational model of the survivin/CDK4 complex that fulfills the experimental evidence and that can be used for structure-based design of inhibitors modifying its interface recognition. In particular, the suggested complex involves the alpha helical domain of survivin and resembles the mode of binding of survivin in the survivin/borealin X-ray structure. The proposed model has been obtained by combining protein-protein docking, fractal-based shape complementarity, electrostatics studies and extensive molecular dynamics simulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Cycle Proteins / chemistry
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 4 / chemistry*
  • Cyclin-Dependent Kinase 6 / chemistry
  • Cyclin-Dependent Kinase Inhibitor p16 / chemistry
  • Humans
  • Inhibitor of Apoptosis Proteins / chemistry*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Neoplasm Proteins / chemistry*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Static Electricity
  • Structural Homology, Protein
  • Survivin

Substances

  • BIRC5 protein, human
  • CDCA8 protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • Survivin
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6