Structural and energetic analysis of human platelet-derived growth factor in complex with MOR-8457 monoclonal antibody using molecular dynamics simulation studies for identification of key interactions

Abstract

Growth factors are natural biomolecules with versatile biological roles in regulation of cell proliferation, organogenesis, migration. Platelet-derived growth factors (PDGFs) are growth factors with mitogenic and chemotactic activity for different cells of mesenchymal origin. In addition to the physiological roles, uncontrolled and overactivated PDGFs especially PDGF-BB signaling has been implicated in a variety of diseases and pathological conditions such as cancers, atherosclerosis, and pulmonary fibrosis. In this context, inhibition of PDGF-BB signaling pathway is of paramount importance in progression of such proliferative diseases. Purpose: Structural and energetic analysis of human platelet-derived growth factor in complex with MOR-8457 monoclonal antibody using molecular dynamics simulation studies for identification of key interactions. Material and methods: Experimental coordinates for the anti PDGF-B monoclonal antibody (MOR-8457) with bound PDGF-BB, by X-ray crystallography was retrieved from the Protein Data Bank for Structural Bioinformatics. In this investigation, for identification of hot spots involved in the interaction of MOR-8457 with PDGF-B, in silico alanine scanning mutagenesis experiment was used. To this end, the important amino acids at the interface of MOR-8457-PDGF-B complex, were mutated to alanine residue using DeepView program. Then, molecular dynamics simulation for the complex of PDGF-B and MOR8457 antibody as well as mutant forms was carried out for 10ns using AMBER package. Finally, binding free energy was calculated for wild type and mutated complexes using MM-PB(GB)SA method implemented in AMBER package. Results: Trp47, Tyr 59, and Trp102 from the heavy chain and Gly28, Tyr30, Phe31, Asp49, Asp50, Phe90, and Asn93 from the light chain of antibody were assigned as hot spots inferred from binding free energy calculations both for antibody mutants and corresponding partners on PDGF-B.

Discussion: The results of the thesis can be used in designing of smaller peptides or peptidomimetics for developing anti-PDGF-B agents where inhibition of PDGF-B signaling is required.