To study the mode and mechanism of interaction of Angiopoietin II with receptor tyrosine kinase Tie-2 using molecular mechanics and molecular dynamics approach

Abstract

BACKGROUD & OBJECTIVE: Angiopoietins are protein growth factors which play key role in Angiogenesis.
Angiogenesis is the process of forming blood vessels from pre-existing ones. Angiopoietin-1 (Ang-1) and Angiopoietin-
2 (Ang-2) have been identified as ligands of the endothelial 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 endothelial-specific
receptor TIE2 and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the
responsiveness of ECs to exogenous cytokines. The transmembrane tyrosine kinase TIE-2 and the receptor for
angiopoietins have been shown to be involved in angiogenic processes. They are also known to play a role in tumor
angiogenesis. However, the mode of interactions between ANG-2 and TIE2 receptor is not known because of the
absence of high resolution co-crystal structure. Therefore in this study attempts were made to investigate the mode and
mechanism of molecular interactions between Tie2 with Ang2 using molecular modeling and molecular dynamics
studies. METHODOLOGY: In the present study, both Tie2 (PDB Id: 2GY5) and Angiopoietins (PDB Id: 2GY7) were
first prepared using protein preparation wizard (Schrodinger package). Protein-protein interaction between both the
proteins was studied using ZDock followed by refinement using Rdock. The best docked pose was then subjected to
Molecular dynamics (MD) simulations to study the precise interaction between TIE2 (Receptor) and Angiopoietin-2
(Ligand) over a specific time span using AMBER 11.0. The obtained MD trajectories were further used to estimate the
binding free energy of the complex using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA)
method. RESULTS: The binding energy (∆Gbinding) between both the proteins, Tie2 and Ang2 was predicted to be -28.77
kcal/mol using Rdock. The other energy parameters between Tie2 and APC interactions such as electrostatic (Eelec), van
der Waals (Evdw) and desolvation (Esol) 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 842:858Å2.
CONCLUSION: Results obtained from this study revealed that both Ang2 and Tie2 bind with high affinity with modest
interacting surface area. Further the results guided us in designing specific experiments for biological evaluations.