To study the mode and mechanism of interaction of A ngiopoietin II with receptor tyrosine kinase Tie-2 using molecular mech anics and molecular dynamics approach

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Year 2013 Vol 2 Issue 1
Document Type : original Article
¹Manya Sharma ² Pradeep Kumar Naik
¹Department of Biotechnology and Bioinformatics, Jaype e University of Information Technology, Waknaghat, Solan-173234, Himachal Pradesh, India
²Department of Biotechnology and Bioinformatics, Jaype e University of Information Technology, Waknaghat, Solan-173234, Himachal Pradesh, India
Abstract
Angiopoietins are protein growth factors which play key role in Angiogenesis. Angiogenesis is the process of forming blood vessel s from pre-existing ones. Angiopoietin-1 (Ang-1) an d Angiopoietin- 2 (Ang-2) have been identified as ligands of the en dothelial receptor tyrosine kinase Tie-2. ANG-2 is a key regulator of angiogenesis that exerts context-dependent effects on endothelial cell (ECs). ANG-2 binds the endotheli al-specific receptor TIE2 and acts as a negative regulator of A NG-1/TIE2 signaling during angiogenesis, thereby co ntrolling the responsiveness of ECs to exogenous cytokines. The tr ansmembrane tyrosine kinase TIE-2 and the receptor for angiopoietins have been shown to be involved in ang iogenic processes. They are also known to play a ro le in tumor angiogenesis. However, the mode of interactions bet ween ANG-2 and TIE2 receptor is not known because o f the absence of high resolution co-crystal structure. Th erefore in this study attempts were made to investi gate the mode and mechanism of molecular interactions between Tie2 wi th Ang2 using molecular modeling and molecular dyna mics studies.

In the present study, both Tie2 (PDB Id: 2GY5) and Angiopoietins (PDB Id: 2GY7) were first prepared using protein preparation wizard (Sc hrodinger package). Protein-protein interaction bet ween both the proteins was studied using ZDock followed by refine ment using Rdock. The best docked pose was then subj ected to Molecular dynamics (MD) simulations to study the pr ecise interaction between TIE2 (Receptor) and Angiop oietin-2 (Ligand) over a specific time span using AMBER 11.0. The obtained MD trajectories were further used to e stimate the binding free energy of the complex using the molecu lar mechanics/Poisson Boltzmann surface area (MM-PBSA ) method .
The binding energy ( ? G binding ) between both the proteins, Tie2 and Ang2 was pred icted to be -28.77 kcal/mol using Rdock. The other energy parameters be tween Tie2 and APC interactions such as electrostati c (E elec ), van der Waals (E vdw ) and desolvation (E sol ) energy are -44.68 kcal/mol, -99.83 kcal/mol and 6 .10 kacal/mol respectively, demonstrating modest interactions between them. The interacting surface area between Tie2 and Ang2 is 842:858Å CONCLUSION: Results obtained from this study revealed that bot h Ang2 and Tie2 bind with high affinity with modest interacting surface area. Further the results guide d us in designing specific experiments for biologic al evaluations.
Keywords
MMPBSA, Molecular Dynamic simulation, Tie2, Angiopo ietin
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