Freie Universität Berlin, Department of Physics, Theoretical Molecular Biophysics Group, Arnimallee 14, D-14195 Berlin, Germany.
Freie Universität Berlin, Department of Physics, Theoretical Molecular Biophysics Group, Arnimallee 14, D-14195 Berlin, Germany; University of Maribor, Faculty of Chemistry and Chemical Engineering, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
J Struct Biol. 2020 Dec 1;212(3):107634. doi: 10.1016/j.jsb.2020.107634. Epub 2020 Sep 29.
Protein and protein-water hydrogen bonds shape the conformational energy landscape of G Protein-Coupled Receptors, GPCRs. As numerous static structures of GPCRs have been solved, the important question arises whether GPCR structures and GPCR conformational dynamics could be described in terms of conserved hydrogen-bond networks, and alterations of these hydrogen-bond networks along the reaction coordinate of the GPCR. To enable efficient analyses of the hydrogen-bond networks of GPCRs we implemented graph-based algorithms, and applied these algorithms to static GPCR structures from structural biology, and from molecular dynamics simulations of two opioid receptors. We find that static GPCR structures tend to have a conserved, core hydrogen-bond network which, when protein and water dynamics are included with simulations, extends to comprise most of the interior of an inactive receptor. In an active receptor, the dynamic protein-water hydrogen-bond network spans the entire receptor, bridging all functional motifs. Such an extensive, dynamic hydrogen-bond network might contribute to the activation mechanism of the GPCR.
蛋白质和蛋白质-水氢键塑造了 G 蛋白偶联受体（GPCR）的构象能量景观。由于已经解决了许多 GPCR 的静态结构，因此出现了一个重要问题，即 GPCR 结构和 GPCR 构象动力学是否可以用保守的氢键网络来描述，以及这些氢键网络沿着 GPCR 反应坐标的变化。为了能够有效地分析 GPCR 的氢键网络，我们实现了基于图的算法，并将这些算法应用于结构生物学中的静态 GPCR 结构，以及两种阿片受体的分子动力学模拟。我们发现，静态 GPCR 结构往往具有保守的核心氢键网络，当包含蛋白质和水动力学的模拟时，该网络扩展到包含无活性受体的大部分内部。在活性受体中，动态蛋白质-水氢键网络跨越整个受体，连接所有功能基序。这种广泛的动态氢键网络可能有助于 GPCR 的激活机制。
