MOLECULAR DYNAMICS STUDY OF STRUCTURAL HLA MICROPOLYMORPHISMS AS A BASIS OF ANT

Carnegie-Mellon University, Pittsburgh PA

Investigators

Linked publications, trials & patents

Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. MHC (major histocompatibility complex) molecules are highly polymorphic molecules which are critical in the self versus non-self discrimination of Immune system. The MHC molecules are comprised of two classes, namely MHC type I (comprised of HLA-A (Human leukocyte antigen), HLA-B and HLA-C molecules) and MHC type II molecules (HLA-DQ, HLA-DR and HLA-DP molecules) which have differing immune system functions. MHC molecules belonging to different families may vary from each other from as few as a couple of amino acids to greater than 30 amino acids. However, the HLA molecules in combination with the peptide presented is highly specific in the recognition of self versus non-self. The structural basis of the same is not well understood and remains a subject of much research. In addition the allelic distribution of these genes underscores the critical role played by the system in protection against microbial invaders of the body. The MHC system also forms the basis for autoimmune diseases whose mechanisms are not well understood. In this study we aim to understand the molecular mechanisms by which HLA micropolymorphisms influence the binding of a viral epitope to the MHC class I (HLA-B*44xx molecules). In addition, configurational information regarding the dynamic structure of the HLA-epitope complex will be analyzed to understand the basis of recognition by the TCR (T-cell receptor) which represents the second half of the antigen-antibody recognition puzzle. The study will use the technique of computational molecular dynamics to understand the role of critical amino acid binding residues in the cleft of HLA-B*44xx molecules. The dynamics of peptide flexibility and plasticity are hypothesized to play a critical role in the immune recognition which is a major focus of this study. We expect the study to provide a major understanding regarding the role of HLA-micropolymorphisms in the recognition and signalling of human immune molecules