Theoretical aspects of designing new vaccines for breast cancer: Docking studies of peptide/HLA-A2.1 complexes

HER2/neu is a transmembrane glycoprotein that is overexpressed in many tumors, including ovarian and breast cancers. The HER2/neu peptide IISAVVGIL (GP2) is recognized by tumor-specific cytotoxic T lymphocytes in the context of human class I major histocompatibility complex (MHC) HLA-A2.1. One limiting-factor for using GP2 as a tumor vaccine is its poor affinity for HLA-A2.1, even though it has the correct peptide-binding motif. The research aims are to develop an accurate docking method for the binding of GP2 to HLA-A2.1, to understand the molecular forces that give rise to strong binding, and to predict mutations that lead to new tumor vaccines. AutoDock and GOLD have been used for docking calculations. The binding free energies from AutoDock correlate qualitatively with experiment. The docked structures for 14 ligands from Autodock3 are in good agreement with experiment. However, the ligands are not fully flexible. GOLD allowed full flexibility to reproduce experimental GP2 structure.