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Structural basis for binding of aurora-AG198N- INCENP complex: MD simulations and free energy calculations

Karunakar Tanneeru1, Lalitha Guruprasad

  • 1School of Chemistry, University of Hyderabad, Hyderabad 500046, India. lgpsc@uohyd.ernet.in.

Protein and Peptide Letters
|July 16, 2013
PubMed

Insights

A Glycine to Asparagine mutation at position 198 in Aurora-A kinase alters its function by enabling binding to INCENP. This study reveals the structural and energetic basis for this Aurora-A(G198N)-INCENP complex formation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Aurora-A, B, and C are serine/threonine kinases crucial for cell division.
  • These kinases are overexpressed in various cancers.
  • A specific mutation (G198N) in Aurora-A kinase alters its function and binding partners, mimicking Aurora-B.

Purpose of the Study:

  • To investigate the molecular mechanisms, structural determinants, and binding energetics of the Aurora-A - INCENP complex following a G198N mutation.
  • To understand how the G198N mutation affects Aurora-A kinase activity and localization.

Main Methods:

  • Molecular docking of INCENP into human Aurora-A kinase.
  • Creation of Aurora-A mutants (G198N, G198L, G198A).
  • 40 ns molecular dynamics (MD) simulations of wild-type and mutant complexes.
  • Analysis of secondary structure fluctuations and solvent accessible surface area.
  • Calculation of binding free energy and solvation free energy.

Main Results:

  • The Asn198 residue forms stabilizing hydrogen bonds within an amphipathic cavity of the Aurora-A(G198N)-INCENP complex.
  • MD simulations revealed distinct interaction patterns and stability among the wild-type and mutant complexes.
  • The Aurora-A(G198N)-INCENP complex exhibited favorable interactions with INCENP, indicated by negative free energy of solvation.

Conclusions:

  • The G198N mutation provides a structural basis for Aurora-A to bind INCENP, altering its kinase function.
  • Hydrogen bonding interactions involving Asn198 are critical for the stability of the Aurora-A(G198N)-INCENP complex.
  • This research elucidates the structural and energetic landscape of the mutated Aurora-A-INCENP interaction, relevant to cancer biology.

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