title: Investigation of the interactions between the EphB2 receptor and SNEW peptide variants.
abstract: EphB2 interacts with cell surface-bound ephrin ligands to relay bidirectional signals. Overexpression of the EphB2 receptor protein has been linked to different types of cancer. The SNEW (SNEWIQPRLPQH) peptide binds with high selectivity and moderate affinity to EphB2, inhibiting Eph-ephrin interactions by competing with ephrin ligands for the EphB2 high-affinity pocket. We used rigorous free energy perturbation (FEP) calculations to re-evaluate the binding interactions of SNEW peptide with the EphB2 receptor, followed by experimental testing of the computational results. Our results provide insight into dynamic interactions of EphB2 with SNEW peptide. While the first four residues of the SNEW peptide are already highly optimized, change of the C-terminal end of the peptide has the potential to improve SNEW-binding affinity. We identified a PXSPY motif that can be similarly aligned with several other EphB2-binding peptides.
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute , Frederick, MD , USA .
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kolb
authors.forename: Michael
authors.initials: M
authors.lastname: Diprima
authors.forename: Molleshree
authors.initials: M
authors.lastname: Karna
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
authors.forename: Qiqi
authors.initials: Q
authors.lastname: Yang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D036183:Receptor, EphB2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D036183:Receptor, EphB2
keywords: EphB2 receptor; ephrin ligands; inhibitor design; molecular dynamics simulations; protein dynamics; protein stability