Energetic and flexibility properties captured by long molecular dynamics simulations of a membrane-embedded pMHCII-TCR complex
Energetic and flexibility properties captured by long molecular dynamics simulations of a membrane-embedded pMHCII-TCR complex
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DOI：
10.1039/c6mb00058d
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发表时间：
2016-01-01
影响因子：
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通讯作者：
Correa-Basurto, Jose
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文献类型：
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作者：
Bello, Martiniano;Correa-Basurto, Jose
尽管晶体学数据已经为pMHC-TCR复合物中的相互作用提供了重要的分子见解，但这种结构方法的固有特征导致其仅提供相互作用的静态图像。虽然无偏分子动力学模拟（UMDS）提供了关于pMHC-TCR复合物的动态结构行为的重要信息，但是它们中的大多数已经将pMHC-TCR复合物建模为可溶的，当在生理条件下时，该复合物是膜结合的;因此，遵循后一UMDS方案可能妨碍重要的动态结果。在这方面的贡献，我们进行了三个独立的300 ns长的UMDS的pMHCII-TCR复合物锚定在两个相对的膜，探索的结构和能量特性的pMHCII的TCR识别。通过UMDS生成的构象系综进行聚类和笛卡尔主成分分析（cPCA），以探索pMHCII-TCR协会的动力学行为。此外，基于通过UMDS采样的构象群体，探索了天然pMHCII-TCR复合物以及天然肽中引入的12个突变（p1-p12 MHCII-TCR）的有效结合自由能、每残基自由能分解和丙氨酸扫描突变。聚类分析和cPCA提供了深入了解TCR到pMHCII上的摇摆运动，以及通过晶体学方法未观察到的新的静电相互作用的存在。有力的结果提供了证据的主要贡献者的pMHC-TCR复合物的形成，以及在这个分子识别过程中涉及的关键残基。
Although crystallographic data have provided important molecular insight into the interactions in the pMHC-TCR complex, the inherent features of this structural approach cause it to only provide a static picture of the interactions. While unbiased molecular dynamics simulations (UMDSs) have provided important information about the dynamic structural behavior of the pMHC-TCR complex, most of them have modeled the pMHC-TCR complex as soluble, when in physiological conditions, this complex is membrane bound; therefore, following this latter UMDS protocol might hamper important dynamic results. In this contribution, we performed three independent 300 ns-long UMDSs of the pMHCII-TCR complex anchored in two opposing membranes to explore the structural and energetic properties of the recognition of pMHCII by the TCR. The conformational ensemble generated through UMDSs was subjected to clustering and Cartesian principal component analyses (cPCA) to explore the dynamical behavior of the pMHCII-TCR association. Furthermore, based on the conformational population sampled through UMDSs, the effective binding free energy, per-residue free energy decomposition, and alanine scanning mutations were explored for the native pMHCII-TCR complex, as well as for 12 mutations (p1-p12MHCII-TCR) introduced in the native peptide. Clustering analyses and cPCA provide insight into the rocking motion of the TCR onto pMHCII, together with the presence of new electrostatic interactions not observed through crystallographic methods. Energetic results provide evidence of the main contributors to the pMHC-TCR complex formation as well as the key residues involved in this molecular recognition process.