Instituto de Física "Luis Rivera Terrazas", Benemérita Universidad Autónoma de Puebla, Av San Claudio, Cd Universitaria, Apdo. Postal J-48, Puebla 72570, México.
J Chem Theory Comput. 2024 Jul 23;20(14):6369-6387. doi: 10.1021/acs.jctc.4c00571. Epub 2024 Jul 11.
G protein-coupled receptors (GPCR) are responsible for modulating various physiological functions and are thus related to the pathophysiology of different diseases. Being potential therapeutic targets, multiple computational methodologies have been developed to analyze their behavior and interactions with other species. The solvent, on the other hand, has received much less attention. In this work, we analyzed the effect of four explicit water models on the structure and interactions of the GPR40 receptor in its apo form. We employed the rigid SPC/E and TIP4P models, and their flexible versions, the FBA/ϵ and TIP4P/ϵ. We explored the structural changes and their correlation with some bulk dynamic properties of water. Our results showed an adverse effect on the conservation of the secondary structure of the receptor with all the models due to the breaking of the intramolecular hydrogen bond network, being more evident for the TIP4P models. Notably, all four models brought the receptor to states similar to the active one, modifying the intracellular part of the TM5 and TM6 domains in a "hinge" type movement, allowing the opening of the structure. Regarding the dynamic properties, the rigid models showed results comparable to those obtained in other studies on membrane systems. However, flexible models exhibit disparities in the molecular representation of systems. Surprisingly, the FBA/ϵ model improves the molecular picture of several properties, even though their agreement with bulk diffusion is poorer. These findings reinforce our idea that exploring other water models or improving the current ones, to better represent the membrane interface, can lead to a positive impact on the description of the signal transduction mechanisms and the search of new drugs by targeting these receptors.
G 蛋白偶联受体（GPCR）负责调节各种生理功能，因此与多种疾病的病理生理学有关。作为潜在的治疗靶点，已经开发出多种计算方法来分析它们与其他物种的相互作用。另一方面，溶剂受到的关注要少得多。在这项工作中，我们分析了四种显式水模型对 GPR40 受体在apo 形式下的结构和相互作用的影响。我们使用了刚性 SPC/E 和 TIP4P 模型及其柔性版本 FBA/ϵ和 TIP4P/ϵ。我们探讨了结构变化及其与一些水的体相动力学性质的相关性。我们的结果表明，由于分子内氢键网络的破坏，所有模型都对受体二级结构的稳定性产生了不利影响，TIP4P 模型更为明显。值得注意的是，所有四个模型都使受体状态类似于激活状态，通过 TM5 和 TM6 结构域的“铰链”型运动来改变细胞内部分，从而使结构开放。关于动态性质，刚性模型显示出与膜系统中其他研究获得的结果相当的结果。然而，柔性模型在系统的分子表示方面存在差异。令人惊讶的是，即使 FBA/ϵ模型与体相扩散的一致性较差，但它仍能改善许多性质的分子图像。这些发现强化了我们的观点，即探索其他水模型或改进当前模型以更好地表示膜界面，可以对信号转导机制的描述以及通过靶向这些受体寻找新药产生积极影响。
