Molecular dynamics-based model of VEGF-A and its heparin interactions

We present a computational model of the Vascular Endothelial Growth Factor (VEGF), an important regulator of blood vessels formation, which function is affected by its heparin interactions. Although structures of a receptor binding (RBD) and a heparin binding domain (HBD) of VEGF are known, there are structural data neither on the 12 amino acids interdomain linker nor on its complexes with heparin. We apply molecular docking and molecular dynamics techniques combined with circular dichroism spectroscopy to model the full structure of the dimeric VEGF and to propose putative molecular mechanisms underlying the function of VEGF/VEGF receptors/heparin system. We show that both the conformational flexibility of the linker and the formation of HBD-heparin-HBD sandwich-like structures regulate the mutual disposition of HBDs and so affect the VEGF-mediated signalling. [Display omitted] •The structure of VEGF interdomain linker was predicted by MD-based approaches.•VEGF interdomain linker structure was analyzed by circular dichroism spectroscopy.•Full structure of VEGF including receptor- and heparin-binding domains was modeled.•Heparin binding modes on the surface of VEGF were predicted and analyzed.•Heparin binding to the VEGF affects the interactions between VEGF and its receptor.