Synergic Effects in the Activation of the Sweet Receptor GPCR Heterodimer for Various Sweeteners Predicted Using Molecular Metadynamics Simulations
Abstract
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.
Additional Information
© 2021 American Chemical Society. Received: June 23, 2021; Revised: August 16, 2021; Accepted: August 20, 2021; Published: October 6, 2021. We thank Dr. Yalu Chen for the original structure preparation. Some computational resources for this research were provided by the Anton 2 computer at the Pittsburgh National Supercomputing Center (MCB180091P). Anton 2 computer time was provided by the Pittsburgh Supercomputing Center (PSC) through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D. E. Shaw Research. This research was supported by grants from the Cargill Corp. with some funding from NIH (R01HL155532). The authors declare no competing financial interest.Attached Files
Supplemental Material - jf1c03779_si_001.pdf
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Additional details
- Eprint ID
- 111329
- DOI
- 10.1021/acs.jafc.1c03779
- Resolver ID
- CaltechAUTHORS:20211008-224624888
- Cargill, Inc.
- R01HL155532
- NIH
- MCB180091P
- Pittsburgh National Supercomputing Center
- R01GM116961
- NIH
- Created
-
2021-10-12Created from EPrint's datestamp field
- Updated
-
2021-11-08Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1492