Conformational Studies of O-Glycosylated 15-Residue Peptide from the Human Mucin (MUC1) Protein Core

Abstract

Certain MUC1 epitopes are detected on MUC1 glycoproteins from malignant cells as opposed to normal cells. The expression of the mucin epitopes appears to be due to the aberrant glycosylation in the tumors resulting in the excessive exposure of the MUC1 protein core on the cell surface. The truncated oligosaccharides of the tumor-derived mucin facilitate antibody binding to this epitope by unmasking the portion of the protein core that is involved in the antibody recognition. A polypeptide fragment APDTRP is known as an immunodominant (ID) region of the MUC1 protein core. To establish a structural rationale for the development of peptide-based tumor markers and vaccines, conformations of the 15-residue peptide PPAHGVTSAPDTRPA and its glycosylated counterpart with GalNAc residue attached at T7 position were studied by molecular dynamics (MD) simulations. The MD simulations in explicit water with and without NMR-derived constraints [1] were used to elucidate the effect of O-glycosyl-ation on conformational propensities of a peptide backbone. Structural propensities of the peptide backbone for the APDTRP fragment were compared with a published crystal structure [2] of the breast tumor-specific antibody SM3 complexed with a 13-residue MUC1 peptide antigen that included this ID region.