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首页> 外文会议>International Conference on Bioinformatics and Biomedical Engineering >Prediction of Functional Types of Ligands for G Protein-Coupled Receptors with Dynamically Discriminable States Embedded in Low Dimension
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Prediction of Functional Types of Ligands for G Protein-Coupled Receptors with Dynamically Discriminable States Embedded in Low Dimension

机译：具有低维动态可分辨状态的G蛋白偶联受体的配体功能类型的预测

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In principle, the differential dynamics of a protein perturbed by various ligands should be able to reflect ligands' different functions. However, in the field of G protein-coupled receptor (GPCR), the phenomenon of conforma-tional heterogeneity, i.e., the sharing of conformations traversed by differently liganded receptors, poses a challenge for delineating ligand's action on perturbing protein dynamics. In a previous work, we have conduct multiple molecular dynamics (MD) simulations of the agonists- and antagonists-bound human A_(2a) adenosine receptor (A_(2a)AR) starting from an intermediate state conformation to maximize the sensitivity of ligand-perturbed dynamics. Conformational heterogeneity can be visualized directly by the Markov state model (MSM) analysis, which is a two-stage procedure first by performing clustering based on conformational similarity to form microstates and then kinetic lumping based on state inter-convertibility to aggregate microstates into macrostates. To delineate the geometric properties of these macrostates, we embedded them onto the low dimensional space constructed with a non-linear dimensionality reduction scheme. While the crystal structures of the G-protein coupled receptor in different states (fully active, intermediate, inactive) can be projected onto divisible regions in the first two dimensions of the isomap embedding, conformations from three "purer" states (agonist-enriched, apo-enriched, antagonist-enriched) cannot be very clearly separated with this two-dimensional embedding. Dimensionality higher than two may still be needed to specify dynamically discriminable states even with nonlinear dimensionality reduction techniques.
机译：原则上，受各种配体干扰的蛋白质的差异动力学应该能够反映配体的不同功能。然而，在G蛋白偶联受体（GPCR）领域，构象异质性的现象，即不同配体受体所遍历的构象的共享，对描述配体对扰动蛋白动力学的作用提出了挑战。在先前的工作中，我们从中间状态构象出发，对激动剂和拮抗剂结合的人A_（2a）腺苷受体（A_（2a）AR）进行了多个分子动力学（MD）模拟，以最大程度地提高配体-扰动的动力学。构象异质性可以通过马尔可夫状态模型（MSM）分析直接可视化，这是一个两阶段过程，首先通过基于构象相似性进行聚类以形成微状态，然后基于状态可互换性进行动态集总以将微状态聚合为宏观状态。为了描述这些宏观状态的几何特性，我们将它们嵌入到使用非线性降维方案构造的低维空间中。虽然可以将处于不同状态（完全活动，中间，无活动）的G蛋白偶联受体的晶体结构投射到isomap嵌入的前两个维度的可分割区域中，但来自三个“纯”状态（富含激动剂，二维嵌入无法非常清楚地分离出apo富集的，拮抗剂富集的）。即使使用非线性降维技术，仍可能需要大于2的维数来指定可动态区分的状态。

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