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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 主要组织相容性复合体(MHC)分子是一种高度多态的分子，在免疫系统的自我与非自我区分中起着至关重要的作用。MHC分子分为两类，即具有不同免疫系统功能的MHC I型分子(包括人类白细胞抗原HLAA、HLAB和HLAC分子)和MHCII型分子(HLADQ、HLADR和HLADP分子)。属于不同家族的MHC分子可能彼此不同，从几个氨基酸到30多个氨基酸不等。然而，与所提供的多肽相结合的人类白细胞抗原分子在识别自我与非自我方面具有高度的特异性。同样的结构基础还没有被很好地理解，仍然是一个许多研究的主题。此外，这些基因的等位基因分布突显了该系统在保护人体免受微生物入侵方面发挥的关键作用。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，我们旨在了解HLA微多态影响病毒表位与MHC I类分子(HLAB*44xx分子)结合的分子机制。此外，还将分析关于HLA-表位复合体动态结构的配置信息，以了解TCR(T细胞受体)识别的基础，TCR(T细胞受体)代表抗原-抗体识别难题的后半部分。这项研究将使用计算分子动力学技术来了解关键氨基酸结合残基在人类白细胞抗原-B*44xx分子裂解中的作用。多肽的柔韧性和可塑性的动力学被认为在免疫识别中起着关键作用，这是本研究的一个主要焦点。我们期望这项研究能对人类免疫分子识别和信号传递中的作用有一个重要的理解。

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