Structural Basis for Binding of Aurora-AG198N- INCENP Complex: MD Simulations and Free Energy Calculations

Author(s): Karunakar Tanneeru, Lalitha Guruprasad.

Journal Name: Protein & Peptide Letters

Volume 20 , Issue 11 , 2013

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Abstract:

Aurora-A, B and C are non-receptor serine/threonine kinases in Homo sapiens. In spite of high similarity in their sequences, they possess distinct binding partners. These kinases play an important role in cell division and overexpressed in certain cancers. It has been demonstrated that Gly198 in Aurora-A kinase is responsible for its basal kinase activity, the mutation G198N transforms Aurora-A to Aurora-B like function and localization by binding to Inner centromere protein (INCENP). The molecular mechanisms, structural determinants and the binding energetics of the Aurora-A – INCENP complex owing to a single amino acid G198N mutation are not studied. Therefore, we have docked INCENP into human Aurora-A kinase, mutated Gly198 to Asn, Leu and Ala. The wild type and mutant Aurora-A – INCENP complexes were subjected to 40 ns molecular dynamics (MD) simulations. The Asn198 is located in the amphipathic cavity comprising Leu869IN, Glu868IN, Thr872IN, Tyr197AurA and Tyr199AurA and the interactions mediated via hydrogen bonds are important to stabilize the Aurora-AG198N – INCENP complex. The fluctuations in the secondary structural elements and the solvent accessible surface area of all the four complexes during the MD simulations were studied. We calculated the binding free energy upon mutation in the three mutant complexes. The Aurora-AG198N – INCENP complex with hydrophilic amino acid mutation has the negative free energy of solvation indicating favorable interactions with INCENP. Our results provide the structural basis and energetics of the human Aurora-AG198N – INCENP complex.

Keywords: Aurora-A kinase, aurora-B kinase, TPX2, INCENP, protein-protein docking, molecular dynamics simulations, mutational free energy.

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Article Details

VOLUME: 20
ISSUE: 11
Year: 2013
Page: [1246 - 1256]
Pages: 11
DOI: 10.2174/09298665113209990045
Price: $65

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