Aureli Simone, Rizzi Valerio, Piasentin Nicola, Gervasio Francesco Luigi
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland.
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CH-1206 Geneva, Switzerland.
J Chem Theory Comput. 2025 Aug 12;21(15):7687-7700. doi: 10.1021/acs.jctc.5c00600. Epub 2025 Jul 28.
The beta-1 adrenergic receptor (ADRB1) is a critical target for cardiovascular drugs, yet our understanding of how it is activated remains incomplete. Capturing the concerted interplay of agonists, solvent, ions, and protein microswitches is a significant challenge for conventional simulation methods and is essential for unraveling this process. Here, we address this challenge by implementing a powerful enhanced sampling framework that integrates the OneOPES enhanced sampling algorithm with a set of biologically motivated collective variables (CVs). These CVs are designed to track several key features of the activation process simultaneously, including rearrangement of conserved microswitches, the state of the sodium ion binding pocket, and dynamics of critical water molecules. Using this framework, we mapped the multidimensional free energy landscapes of the ADRB1 receptor in both its apo- and adrenaline-bound holo states. Our analysis reveals a detailed, stepwise activation pathway that quantifies the known modulatory roles of sodium ions and protonation states and identifies essential water-mediated networks that stabilize the active conformation. This work provides a detailed overview of ADRB1 activation and establishes the robustness of our OneOPES approach for investigating complex activation mechanisms with the potential for application to other Class A GPCRs.
β-1肾上腺素能受体（ADRB1）是心血管药物的关键靶点，但我们对其激活方式的理解仍不完整。捕捉激动剂、溶剂、离子和蛋白质微开关之间的协同相互作用，对传统模拟方法来说是一项重大挑战，而对于阐明这一过程至关重要。在这里，我们通过实施一个强大的增强采样框架来应对这一挑战，该框架将OneOPES增强采样算法与一组具有生物学动机的集体变量（CVs）相结合。这些CVs旨在同时跟踪激活过程的几个关键特征，包括保守微开关的重排、钠离子结合口袋的状态以及关键水分子的动力学。使用这个框架，我们绘制了ADRB1受体在其无配体和肾上腺素结合的全态下的多维自由能景观。我们的分析揭示了一条详细的、逐步的激活途径，该途径量化了钠离子和质子化状态的已知调节作用，并确定了稳定活性构象的关键水介导网络。这项工作提供了ADRB1激活的详细概述，并确立了我们的OneOPES方法在研究复杂激活机制方面的稳健性，有可能应用于其他A类G蛋白偶联受体。
