Structural and energetic analysis of human platelet-derived growth factor in complex with its receptor using molecular dynamics simulation studies for identification of key interactions

Abstract

Platelet-derived growth factor (PDGF) is a family of growth factors that is released mainly from platelets during tissue damage and bone fractures, which can exert various functions such as proliferation, cell migration, wound healing, … through binding to the corresponding receptors. Several studies indicted that uncontrolled and overactivated PDGF signaling has been implicated in a variety of diseases, such as cancers, atherosclerosis, and pulmonary fibrosis. In this context, inhibition of PDGF-PDGFR signaling is of paramount importance in progression of such diseases. Purpose: Structural and energetic analysis of human platelet-derived growth factor in complex with its receptor using molecular dynamics simulation studies for identification of key interactions. Material and methods: In this study, molecular dynamics simulation for the experimentally determined 3D structure of PDGF-BB in complex with PDGFR-β was performed for 10 ns using AMBER package. Then, the alanine scanning mutagenesis was used for identification of important amino acids involved in the interactions. Finally, the binding free energy for the complex and each of the mutants was calculated using MM-PBSA method. Results: Residues Arg27, Arg28, Thr33, Asn34, Asn36, Phe37, Leu38, Trp40, Asn54, Asn55, Arg73, Ile77, Arg79, Lys80, Lys98, Cys99 and Thr101 from platelet-derived growth factor and residues Phe136, Thr140, Glu184, Arg186, Tyr205, Glu241, Val242, Val243, Phe245, Pro260, Val261, Thr262, Ser296 and Val297 from the PDGFR-β receptor were assigned as hot spots deduced from calculated binding free energies both for PDGF-BB mutants and corresponding partners on PDGFR-β. Discussion: The results of this study can be used to design peptidomimetics capable of binding to PDGF-BB or its receptor. The design of such molecules can be beneficial in diseases associated with overactivated PDGF signaling pathways.