Conformational flexibility of the MHC class I alpha1-alpha2 domain in peptide bound and free states: a molecular dynamics simulation study.
Conformational flexibility of the MHC class I alpha1-alpha2 domain in peptide bound and free states: a molecular dynamics simulation study.
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MHC I 类 α1-α2 结构域在肽结合和游离状态下的构象灵活性：分子动力学模拟研究。
作者：
M. Zacharias;S. Springer
主要组织相容性复合物I类蛋白在肽抗原识别和呈递给宿主免疫系统中起关键作用。各种主要组织相容性复合物I类蛋白质的结构已通过实验与几种抗原肽复合确定。然而，未结合（空）形式的结构是未知的。为了研究空的主要组织相容性复合体I类分子的构象动力学，比较分子动力学模拟已经从肽结合的I类肽结合结构域的晶体结构中的肽配体的存在和不存在下进行。包括结合肽的模拟在26 ns的整个模拟期间在两个模拟温度（300和355 K）下保持接近实验起始结构。在不存在肽的情况下的几个独立模拟表明，空结构域可能不采用单一限定的构象，而是在构象上显著更异质，特别是在肽结合裂缝侧翼的α-螺旋内。计算的构象动力学沿着的蛋白质链相关以及与可用的光谱数据和所观察到的位点特异性的空I类蛋白质的蛋白水解消化的敏感性。在300 K的模拟过程中，肽N-末端的结合区域保持接近于结合状态下的构象，而C-末端的锚区域显示出显著更大的构象波动。这包括结构域中第二个α-螺旋开始处的片段，该片段可能在肽加载过程中参与与伴侣蛋白tapasin的相互作用。模拟研究进一步表明，在C-和N-末端的肽结合可能遵循不同的机制，涉及不同程度的诱导构象变化的肽结合结构域。特别地，肽C-末端的结合可能需要在肽加载期间通过伴侣蛋白进行构象稳定。
Major histocompatibility complex class I proteins play a key role in the recognition and presentation of peptide antigens to the host immune system. The structure of various major histocompatibility complex class I proteins has been determined experimentally in complex with several antigenic peptides. However, the structure in the unbound (empty) form is not known. To study the conformational dynamics of the empty major histocompatibility complex class I molecule comparative molecular dynamics simulations have been performed starting from the crystal structure of a peptide bound class I peptide-binding domain in the presence and absence of a peptide ligand. Simulations including the bound peptide stayed close to the experimental start structure at both simulation temperatures (300 and 355 K) during the entire simulation of 26 ns. Several independent simulations in the absence of peptide indicate that the empty domain may not adopt a single defined conformation but is conformationally significantly more heterogeneous in particular within the alpha-helices that flank the peptide binding cleft. The calculated conformational dynamics along the protein chain correlate well with available spectroscopic data and with the observed site-specific sensitivity of the empty class I protein to proteolytic digestion. During the simulations at 300 K the binding region for the peptide N-terminus stayed close to the conformation in the bound state, whereas the anchor region for the C-terminus showed significantly larger conformational fluctuations. This included a segment at the beginning of the second alpha-helix in the domain that is likely to be involved in the interaction with the chaperone protein tapasin during the peptide-loading process. The simulation studies further indicate that peptide binding at the C- and N-terminus may follow different mechanisms that involve different degrees of induced conformational changes in the peptide-binding domain. In particular binding of the peptide C-terminus may require conformational stabilization by chaperone proteins during peptide loading.
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DOI：
--
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