Department of Chemistry and Biochemistry, California State University, Northridge, CA, United States.
Department of Chemistry and Biochemistry, California State University, Northridge, CA, United States.
Adv Protein Chem Struct Biol. 2022;128:325-359. doi: 10.1016/bs.apcsb.2021.11.001. Epub 2021 Dec 20.
G protein-coupled receptors (GPCRs) make up the largest superfamily of integral membrane proteins and play critical signal transduction roles in many physiological processes. Developments in molecular biology, biophysical, biochemical, pharmacological, and computational techniques aimed at these important therapeutic targets are beginning to provide unprecedented details on the structural as well as functional basis of their pleiotropic signaling mediated by G proteins, β arrestins, and other transducers. This pleiotropy presents a pharmacological challenge as the same ligand-receptor interaction can cause a therapeutic effect as well as an undesirable on-target side-effect through different downstream pathways. GPCRs don't function as simple binary on-off switches but as finely tuned shape-shifting machines described by conformational ensembles, where unique subsets of conformations may be responsible for specific signaling cascades. X-ray crystallography and more recently cryo-electron microscopy are providing snapshots of some of these functionally-important receptor conformations bound to ligands and/or transducers, which are being utilized by computational methods to describe the dynamic conformational energy landscape of GPCRs. In this chapter, we review the progress in computational conformational sampling methods based on molecular dynamics and discrete sampling approaches that have been successful in complementing biophysical and biochemical studies on these receptors in terms of their activation mechanisms, allosteric effects, actions of biased ligands, and effects of pathological mutations. Some of the sampled simulation time scales are beginning to approach receptor activation time scales. The list of conformational sampling methods and example uses discussed is not exhaustive but includes representative examples that have pushed the limits of classical molecular dynamics and discrete sampling methods to describe the activation energy landscape of GPCRs.
G 蛋白偶联受体（GPCRs）构成了最大的整合膜蛋白超家族，在许多生理过程中发挥着关键的信号转导作用。旨在针对这些重要治疗靶点的分子生物学、生物物理、生物化学、药理学和计算技术的发展，开始为 G 蛋白、β 抑制蛋白和其他转导蛋白介导的其多效信号的结构和功能基础提供前所未有的细节。这种多效性带来了药理学上的挑战，因为相同的配体-受体相互作用既可以通过不同的下游途径产生治疗效果，也可以产生不理想的靶副作用。GPCR 不是简单的二元开/关开关，而是作为精细调节的形状转换机器，由构象集合来描述，其中独特的构象子集可能负责特定的信号级联。X 射线晶体学和最近的冷冻电子显微镜为一些结合配体和/或转导蛋白的具有功能重要性的受体构象提供了快照，这些构象正在被计算方法用于描述 GPCR 的动态构象能量景观。在本章中，我们回顾了基于分子动力学和离散采样方法的计算构象采样方法的进展，这些方法在这些受体的激活机制、变构效应、偏倚配体的作用以及病理突变的影响方面成功地补充了生物物理和生物化学研究。一些采样模拟时间尺度开始接近受体激活时间尺度。所讨论的构象采样方法和示例使用列表并不是详尽无遗的，但包括了代表的示例，这些示例已经推动了经典分子动力学和离散采样方法的极限，以描述 GPCR 的激活能量景观。
