Unraveling the Allosteric Communication Mechanisms in T-Cell Receptor-Peptide-Loaded Major Histocompatibility Complex Dynamics Using Molecular Dynamics Simulations: An Approach Based on Dynamic Cross Correlation Maps and Residue Interaction Energy Calculations
Unraveling the Allosteric Communication Mechanisms in T-Cell Receptor-Peptide-Loaded Major Histocompatibility Complex Dynamics Using Molecular Dynamics Simulations: An Approach Based on Dynamic Cross Correlation Maps and Residue Interaction Energy Calculations
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DOI：
10.1021/acs.jcim.1c00338
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发表时间：
2021-04-30
影响因子：
5.6
通讯作者：
Ozbek, Pemra
中科院分区：
文献类型：
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作者：
Bingol, Elif Naz;Sercinoglu, Onur;Ozbek, Pemra
由主要组织相容性复合体（MHC）蛋白向T细胞受体（TCR）的抗原呈递在触发适应性免疫应答中起关键作用。我们对TCR-肽负载的主要组织相容性复合物（pMHC）相互作用的大部分知识源于产生静态结构的实验，然而这种分子相互作用的动态方面对于理解潜在的分子机制和开发针对疾病（如癌症和自身免疫性疾病）的治疗策略同样重要。为此，包括全原子分子动力学模拟在内的计算生物物理学研究提供了有用的见解;然而，我们仍然缺乏对导致TCR构象变化和随后的T细胞活化的整体变构机制的基本理解。先前的氢-氘交换和核磁共振研究提供了关于这些分子机制的线索，包括对远离pMHC相互作用位点的TCR恒定结构域的全局硬化和变构效应。在这里，我们表明，分子动力学模拟可以用来确定如何整体硬化可能与变构通信后，通过基本动力学和非键残基-残基相互作用能量分析pMHC相互作用的TCR内。通过对残基相互作用变化的复杂分析，突出了参与硬化效应的残基，从而详细描述了复合物的形成过程。我们的研究结果表明，TCR的C β结构域的残基在复合物形成后的非键合相互作用中显示出显着差异。此外，这些残基之间的动态交叉相关性也增加，符合它们的非键相互作用能的变化。总之，我们的方法可能是有价值的阐明分子内变构变化的TCR结构后，在分子动力学模拟中的pMHC相互作用。
Antigen presentation by major histocompatibility complex (MHC) proteins to T-cell receptors (TCRs) plays a crucial role in triggering the adaptive immune response. Most of our knowledge on TCR-peptide-loaded major histocompatibility complex (pMHC) interaction stemmed from experiments yielding static structures, yet the dynamic aspects of this molecular interaction are equally important to understand the underlying molecular mechanisms and to develop treatment strategies against diseases such as cancer and autoimmune diseases. To this end, computational biophysics studies including all-atom molecular dynamics simulations have provided useful insights; however, we still lack a basic understanding of an overall allosteric mechanism that results in conformational changes in the TCR and subsequent T-cell activation. Previous hydrogen-deuterium exchange and nuclear magnetic resonance studies provided clues regarding these molecular mechanisms, including global rigidification and allosteric effects on the constant domain of TCRs away from the pMHC interaction site. Here, we show that molecular dynamics simulations can be used to identify how this overall rigidification may be related to the allosteric communication within TCRs upon pMHC interaction via essential dynamics and nonbonded residue-residue interaction energy analyses. The residues taking part in the rigidification effect are highlighted with an intricate analysis on residue interaction changes, which lead to a detailed outline of the complex formation event. Our results indicate that residues of the C beta domain of TCRs show significant differences in their nonbonded interactions upon complex formation. Moreover, the dynamic cross correlations between these residues are also increased, in line with their nonbonded interaction energy changes. Altogether, our approach may be valuable for elucidating intramolecular allosteric changes in the TCR structure upon pMHC interaction in molecular dynamics simulations.