Synergic Effects in the Activation of the Sweet Receptor GPCR Heterodimer for Various Sweeteners Predicted Using Molecular Metadynamics Simulations,Journal of Agricultural and Food Chemistry

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Synergic Effects in the Activation of the Sweet Receptor GPCR Heterodimer for Various Sweeteners Predicted Using Molecular Metadynamics Simulations
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2021-10-06 , DOI: 10.1021/acs.jafc.1c03779
Jaewan Jang ₁ , Soo-Kyung Kim ₁ , Brian Guthrie ₂ , William A Goddard ₁

Affiliation

The sweet taste is elicited by activation of the TAS1R2/1R3 heterodimer G protein-coupled receptor. This is a therapeutic target for treatment of obesity and metabolic dysfunctions. Sweetener blends provide attractive strategies to lower the sugar level while preserving the attractive taste of food. To understand the synergic effect of various sweetener blend combinations of artificial and natural sweeteners, we carried out our molecular dynamics studies using predicted structures of the TAS1R2/1R3 heterodimer and predicted structures for the sweeteners. We used as a measure of activation the intracellular ionic lock distance between transmembrane helices 3 and 6 of TAS1R3. We find that full synergic combinations [rebaudioside A (Reb-A)/acesulfame K and Reb-A/sucralose] and partial synergic combinations (sucralose/acesulfame K) show significantly more negative changes in the free energy compared to single-ligand cases, while a pair known to be suppressive (saccharin and acesulfame K) shows significantly less changes than for the single-ligand case. This study provides an atomistic understanding of the mechanism for synergy and identifies new combinations of sweeteners to reduce the caloric content for treating diseases.

中文翻译：

使用分子元动力学模拟预测的各种甜味剂的甜味受体 GPCR 异二聚体活化的协同效应

甜味是通过激活 TAS1R2/1R3 异二聚体 G 蛋白偶联受体引起的。这是治疗肥胖症和代谢功能障碍的治疗靶点。甜味剂混合物提供了有吸引力的策略来降低糖含量，同时保持食物的诱人味道。为了了解人工和天然甜味剂的各种甜味剂混合物组合的协同效应，我们使用 TAS1R2/1R3 异二聚体的预测结构和甜味剂的预测结构进行了分子动力学研究。我们使用 TAS1R3 跨膜螺旋 3 和 6 之间的细胞内离子锁距离作为激活的度量。我们发现完全协同组合 [莱鲍迪苷 A (Reb-A)/安赛蜜 K 和 Reb-A/三氯蔗糖] 和部分协同组合（三氯蔗糖/安赛蜜 K）与单配体情况相比，在自由能方面表现出明显更多的负面变化，而已知具有抑制作用的一对（糖精和乙酰磺胺酸钾）显示出的变化比单配体情况要少得多。这项研究提供了对协同作用机制的原子理解，并确定了甜味剂的新组合，以降低治疗疾病的热量含量。

更新日期：2021-10-20

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