Class I major histocompatibility complex (MHC) molecules are cell surface glycoproteins that bind short peptide fragments and present them to cytotoxic T lymphocytes. This antigen presentation mechanism operates in most nucleated cells and provides an important means for the immune system to detect and eliminate virally infected or tumor cells. The ability to predict peptide sequences that are capable of binding to MHC class I molecules is a crucial step toward establishing CTL-based immunotherapies and rational vaccine design.; The binding of peptides to MHC molecule is both specific and promiscuous. It is specific in the sense that an MHC molecule encoded by a specific allele will bind certain peptides but not others, and it is promiscuous in the sense that different peptide sequences might bind to the same MHC molecule. It was shown that sequence diversity in the central region of the peptide is accommodated by a combination of flexibility of polymorphic MHC residues at the bottom of the groove and variation of bound water molecules underneath the peptide. Hence, determining the precise binding interactions of peptide-MHC complexes requires consideration of the structural water molecules and the flexibility of MHC sidechains in the peptide binding site.; In this research, a computer algorithm was developed to predict binding interactions of peptide-MHC class I complexes. The success of the MHC algorithm in predicting structures of peptide-HLA-A2 complexes was shown to depend on three critical factors: (1) adequate sampling of peptide backbone conformations, (2) flexibility of MHC sidechains, and (3) modeling of explicit interface water molecules.
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