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

J Mol Graph Model. 2018 Jun:82:157-166. doi: 10.1016/j.jmgm.2018.04.015. Epub 2018 Apr 27.

Abstract

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.

Keywords: Circular dichroism spectroscopy; Molecular docking; Protein-glycosaminoglycan interactions; Replica exchange molecular dynamics; VEGF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Circular Dichroism
  • Heparin / chemistry*
  • Heparin / metabolism
  • Humans
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Peptides / chemistry
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Vascular Endothelial Growth Factor A / chemistry*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Peptides
  • Vascular Endothelial Growth Factor A
  • Heparin