BACKGROUND T cell receptor (TCR) molecules are involved in the adaptive immune response as they distinguish between self- and foreign-peptides, presented in major histocompatibility complex molecules (pMHC). Former studies showed that the association angles of the TCR variable domains (Vα/Vβ) can differ significantly and change upon binding to the pMHC complex. These changes can be described as a rotation of the domains around a general Center of Rotation, characterized by the interaction of two highly conserved glutamine residues. METHODS We developed a computational method, DynaDom, for the prediction of TCR Vα/Vβ inter-domain and TCR/pMHC orientations in TCRpMHC complexes, which allows predicting the orientation of multiple protein-domains. In addition, we implemented a new approach to predict the correct orientation of the carboxamide endgroups in glutamine and asparagine residues, which can also be used as an external, independent tool. RESULTS The approach was evaluated for the remodeling of 75 and 53 experimental structures of TCR and TCRpMHC (class I) complexes, respectively. We show that the DynaDom method predicts the correct orientation of the TCR Vα/Vβ angles in 96 and 89% of the cases, for the poses with the best RMSD and best interaction energy, respectively. For the concurrent prediction of the TCR Vα/Vβ and pMHC orientations, the respective rates reached 74 and 72%. Through an exhaustive analysis, we could show that the pMHC placement can be further improved by a straightforward, yet very time intensive extension of the current approach. CONCLUSIONS The results obtained in the present remodeling study prove the suitability of our approach for interdomain-angle optimization. In addition, the high prediction rate obtained specifically for the energetically highest ranked poses further demonstrates that our method is a powerful candidate for blind prediction. Therefore it should be well suited as part of any accurate atomistic modeling pipeline for TCRpMHC complexes and potentially other large molecular assemblies.

中文翻译：

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DynaDom：T细胞受体域间和T细胞受体-肽-MHC（I类）关联角的基于结构的预测。

背景技术由于T细胞受体（TCR）分子区分主要组织相容性复合物分子（pMHC）中存在的自身肽和外源肽，因此它们参与了适应性免疫应答。以前的研究表明，TCR可变域（Vα/Vβ）的缔合角可以显着不同，并且在与pMHC复合物结合后会发生变化。这些变化可以描述为围绕总体旋转中心的域旋转，其特征在于两个高度保守的谷氨酰胺残基的相互作用。方法我们开发了一种计算方法DynaDom，用于预测TCRpMHC复合物中TCRVα/Vβ域间和TCR / pMHC方向，从而可以预测多个蛋白质结构域的方向。此外，我们实施了一种新方法来预测谷氨酰胺和天冬酰胺残基中羧酰胺端基的正确方向，也可以用作外部独立工具。结果评估了该方法分别对TCR和TCRpMHC（I类）复合物的75和53个实验结构的重塑。我们显示，对于分别具有最佳RMSD和最佳交互作用能量的姿势，DynaDom方法可预测96％和89％的情况下TCRVα/Vβ角的正确方向。为了同时预测TCRVα/Vβ和pMHC方向，各自的比率分别达到74％和72％。通过详尽的分析，我们可以证明，通过对当前方法的直接但非常耗时的扩展，可以进一步改善pMHC的位置。结论在本次改造研究中获得的结果证明了我们的方法适用于域间角度优化的适用性。此外，专为能量最高排名的姿势而获得的高预测率进一步表明，我们的方法是盲目预测的有力候选者。因此，它应该非常适合作为TCRpMHC配合物和其他潜在大分子组装体的任何精确原子建模管道的一部分。