Atomistic Insights into Rhodopsin Activation from a Dynamic Model

Rhodopsin, the light sensitive receptor responsible for blue-green vision, serves as a prototypical G protein-coupled receptor (GPCR). Upon light absorption, it undergoes a series of conformational changes that lead to the active form, metarhodopsin II (META II), initiating a signaling cascade through binding to the G protein transducin (Gt). Here, we first develop a structural model of META II by applying experimental distance restraints to the structure of lumi-rhodopsin (LUMI), an earlier intermediate. The restraints are imposed by using a combination of biased molecular dynamics simulations and perturbations to an elastic network model. We characterize the motions of the transmembrane helices in the LUMI-to-META II transition and the rearrangement of interhelical hydrogen bonds. We then simulate rhodopsin activation in a dynamic model to study the path leading from LUMI to our META II model for wild-type rhodopsin and a series of mutants. The simulations show a strong correlation between the transition dynamics and the pharmacological phenotypes of the mutants. These results help identify the molecular mechanisms of activation in both wild type and mutant rhodopsin. While static models can provide insights into the mechanisms of ligand recognition and predict ligand affinity, a dynamic model of activation could be applicable to study the pharmacology of other GPCRs and their ligands, offering a key to predictions of basal activity and ligand efficacy.

视紫红质（Rhodopsin）是介导蓝绿色视觉的光敏感受体，同时也是典型的G蛋白偶联受体（G protein-coupled receptor, GPCR）。在吸收光子后，视紫红质会经历一系列构象变化，最终转变为激活态形式——偏视紫红质II（metarhodopsin II, META II），并通过与G蛋白转导蛋白（transducin, Gt）结合启动信号级联反应。本研究首先以早期中间体光视紫红质（lumi-rhodopsin, LUMI）的结构为基础，通过施加实验距离约束构建偏视紫红质II的结构模型。该约束通过结合偏置分子动力学模拟与弹性网络模型微扰的方式施加。我们对光视紫红质向偏视紫红质II转变过程中的跨膜螺旋运动以及螺旋间氢键重排进行了表征。随后，我们在动态模型中模拟视紫红质的激活过程，以探究野生型视紫红质及一系列突变体从光视紫红质转变为我们所构建的偏视紫红质II模型的通路。模拟结果显示，转变动力学过程与突变体的药理学表型之间存在显著相关性。上述结果有助于阐明野生型与突变型视紫红质的激活分子机制。尽管静态模型能够为配体识别机制提供见解并预测配体亲和力，但激活动态模型可用于研究其他G蛋白偶联受体及其配体的药理学特性，为预测基础活性与配体效能提供关键思路。