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

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 主要组织相容性复合体（major histocompatibility complex，MHC）分子是一种高度多态性的分子，在免疫系统自我与非自我的识别中起着关键作用。MHC分子由两类组成，即具有不同免疫系统功能的MHC I型（由HLA-A（人类白细胞抗原）、HLA-B和HLA-C分子组成）和MHC II型分子（HLA-DQ、HLA-DR和HLA-DP分子）。属于不同家族的MHC分子可以彼此不同，从少至几个氨基酸到大于30个氨基酸。然而，HLA分子与呈递的肽的组合在识别自身与非自身方面是高度特异性的。同样的结构基础还没有得到很好的理解，仍然是一个大量研究的主题。此外，这些基因的等位基因分布强调了该系统在保护机体免受微生物入侵方面所发挥的关键作用。MHC系统也是自身免疫性疾病的基础，其机制尚不清楚。在这项研究中，我们的目的是了解HLA微多态性影响病毒表位与MHC I类（HLA-B* 44 xx分子）结合的分子机制。此外，将分析有关HLA-表位复合物的动态结构的构型信息，以了解代表抗原-抗体识别难题的第二部分的TCR（T细胞受体）的识别基础。该研究将使用计算分子动力学技术来了解HLA-B* 44 xx分子裂缝中关键氨基酸结合残基的作用。肽的灵活性和可塑性的动力学被假设在免疫识别中起着关键作用，这是本研究的一个主要焦点。我们希望这项研究能够提供一个关于HLA微多态性在人类免疫分子识别和信号传导中的作用的主要理解

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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