Basith Shaherin, Lee Yoonji, Choi Sun
National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
Methods Mol Biol. 2018;1762:455-472. doi: 10.1007/978-1-4939-7756-7_23.
Unraveling the mystery of protein allostery has been one of the greatest challenges in both structural and computational biology. However, recent advances in computational methods, particularly molecular dynamics (MD) simulations, have led to its utility as a powerful and popular tool for the study of protein allostery. By capturing the motions of a protein's constituent atoms, simulations can enable the discovery of allosteric hot spots and the determination of the mechanistic basis for allostery. These structural and dynamic studies can provide a foundation for a wide range of applications, including rational drug design and protein engineering. In our laboratory, the use of MD simulations and network analysis assisted in the elucidation of the allosteric hotspots and intracellular signal transduction of G protein-coupled receptors (GPCRs), primarily on one of the adenosine receptor subtypes, A adenosine receptor (AAR). In this chapter, we describe a method for calculating the map of allosteric signal flow in different GPCR conformational states and illustrate how these concepts have been utilized in understanding the mechanism of GPCR allostery. These structural studies will provide valuable insights into the allosteric and orthosteric modulations that would be of great help to design novel drugs targeting GPCRs in pathological states.
揭开蛋白质别构的奥秘一直是结构生物学和计算生物学领域面临的最大挑战之一。然而，计算方法的最新进展，尤其是分子动力学（MD）模拟，使其成为研究蛋白质别构的一种强大且常用的工具。通过捕捉蛋白质组成原子的运动，模拟能够发现别构热点并确定别构的机制基础。这些结构和动力学研究可为广泛的应用提供基础，包括合理药物设计和蛋白质工程。在我们实验室，MD模拟和网络分析的应用有助于阐明G蛋白偶联受体（GPCR）的别构热点和细胞内信号转导，主要针对腺苷受体亚型之一，即A1腺苷受体（A1AR）。在本章中，我们描述了一种计算不同GPCR构象状态下别构信号流图谱的方法，并说明这些概念如何用于理解GPCR别构机制。这些结构研究将为别构和正构调节提供有价值的见解，这对设计针对病理状态下GPCR的新型药物有很大帮助。
