Albany 2001

category image Biomolecular
SUNY at Albany
June 19-23, 2001

Structural and computational studies of a class II MHC complex with a nonconforming peptide

The stable binding of processed foreign peptide to a class II major histocompatibility (MHC) molecule and subsequent presentation to cognate T cell receptor (TCR) is important for signalling intracellular infection and for inducing helper signals. This is a central event in immune recognition and regulation. Polymorphic residues on the floor of the peptide binding site form pockets that anchor peptide side chains. These and other polymorphic residues in the alpha-helical wall of the groove determine the binding specificity of each allele and define a motif. Allele specific motifs allow the prediction of potential epitopes from the sequences of pathogen proteins. There are, however, several known epitopes which do not satisfy these motifs. There is evidence that anchor motifs are not adequate for predicting which peptides bind as there are apparently major and minor motifs. We have begun crystallographic studies in order to understand the nature of the interactions that govern the binding of these so called nonconforming peptides to human leukocyte antigen DR (HLA-DR). We would like to understand the role of the motifs in peptide binding. We would like to find out whether the peptides that do not obey the consensus anchor motif bind in the canonical conformation observed in all structures of class II MHC-peptide complexes determined so far. We are complementing our studies with dynamical and molecular modelling. We shall employ long time simulations to answer these questions, particularly the interplay of the anchor motifs in peptide binding, to explore the range of conformations available tothe bound peptide and to understand the water hydration structures mediating binding.

Christian S. Parry and Lawrence J. Stern,

Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139-4307
email: stern@mit.edu; tel: (617)253-2849; fax: (617)258-7847