title: Affinity enhancement of HER2-binding Z(HER2:342) affibody via rational design approach: a molecular dynamics study.
abstract: Human epidermal growth factor receptor 2 (HER2) contributes to the development of breast cancers and malignancies. On the other hand, engineered affibody Z(HER2:342) that binds to HER2 can be successfully used for both diagnostic purposes and specific ablation of malignant HER2-positive cell lines. In the current study, electrostatics-based prediction was applied for improving Z(HER2:342) binding affinity using computational design. The affibody Z(HER2:342) alone and in complex with HER2 was energetically minimized, solvated in explicit water, and neutralized. After heating and equilibration steps, the system was studied by isothermal-isobaric (NPT) MD simulation. According to trajectories, Z(HER2:342) specifically binds to HER2 through hydrogen bonds and salt bridges. Based on the electrostatic binding contributions, two affinity-matured variants namely V1 (Tyr35Arg) and V2 (Asn6Asp and Met9Glu) were rationally designed. More investigations through MD simulation show that V1 interacts with HER2 receptor more strongly, compared to Z(HER2:342) and V2.
authors.affiliation: a Department of Biochemistry , Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran .
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Ghaffari
authors.forename: Majid
authors.initials: M
authors.lastname: Zeinali
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Barzegari Asadabadi
authors.forename: Mostafa
authors.initials: M
authors.lastname: Jamalan
authors.forename: Samad
authors.initials: S
authors.lastname: Jahandideh
mesh_terms: D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D017433:Protein Structure, Secondary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C533351:affibody (ZHER2-342)2; C508053:ERBB2 protein, human
keywords: EGFRs; Z(HER2:342) affibody; affinity enhancement; molecular dynamics simulation