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Vivien J. Coulson- Thomas, Osamu Yamanaka, Yong Yuan, Tarsis Ferreira Gesteira, Chia-Yang Liu, Winston Kao; Computational Studies of potential binding sites for Small Leucine Rich Proteoglycan to Growth Factor Receptors. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4204.
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© ARVO (1962-2015); The Authors (2016-present)
Smallleucine rich proteoglycans (SLRPs) orchestrate collagen fibillogenesis contributing to the formation of a transparent cornea. SLRPs have also been shown to play an important role in modulating signaling pathways, mediating inflammatory response and regulating cell migration, and, play an important role in corneal wound healing. Recent studies implicate the involvement of decorin in the EGFR signaling pathway, as well as, the role of keratocan and lumican in mediating TBR1 and CXCL1 signaling. A combined molecular docking and molecular dynamics approach was employed to study the binding kinetics of these SLRPs on the aforementioned receptors. Moreover, we attempt to predict vital derivativepeptides involved in the binding.
Coordinates of lumican and keratocan were built using MODELLER 9v8 using bovine decorin (1XKU) structure as template. Lumican and keratocan were docked to TBRI and decorin was docked to EGFR and FGFR using the macro docking option of Hex 4.5, as well as, Haddock v2.1 to model biomolecular complexes. The molecular dynamics (MD) simulation, as well as, trajectory and interaction energy analysis were performed using the GROMACS v 4.5.1 simulation suite. The final complexes were analyzed using with Pymol 1.4 and VMD v1.8.6. Finally, a model of the whole TBR1 molecule inserted into a bilayer membrane consisting of 200 1-palmitoyl-2-oleoylphosphatidylcholine/35 water molecules was created using g_membed.
The c-terminal ear loop of lumican bound to the GS domain of TBRI. Analyzing the MT1-MMP cleavage sites, a 53 amino acid c-terminal portion of lumican docked to TGFβRI with an energy of -1.086 kJ/mol. The 63 amino acid c-terminal portion of keratocan also binds to TBR1. Decorin binds to the extracellular portion of EGFR dimer complex, however, binds to FGFR with no reasonable binding energy.
The C-terminal region of lumican binds to the GS domain of TBR1, moreover, we were able to determine the precise amino acids sequences involved in this binding. Based on our results docking is a relevant screening assay to predict binding sites and evaluate binding affinity for SLRPs to growth factor receptors.
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