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Synergic Effects in the Activation of the Sweet Receptor GPCR Heterodimer for Various Sweeteners Predicted Using Molecular Metadynamics Simulations

Jang, Jaewan and Kim, Soo-Kyung and Guthrie, Brian and Goddard, William A., III (2021) 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, 69 (41). pp. 12250-12261. ISSN 0021-8561. doi:10.1021/acs.jafc.1c03779. https://resolver.caltech.edu/CaltechAUTHORS:20211008-224624888

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.jafc.1c03779DOIArticle
ORCID:
AuthorORCID
Jang, Jaewan0000-0003-0595-6506
Kim, Soo-Kyung0000-0002-4498-5441
Guthrie, Brian0000-0002-3508-4625
Goddard, William A., III0000-0003-0097-5716
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.
Funders:
Funding AgencyGrant Number
Cargill, Inc.UNSPECIFIED
NIHR01HL155532
Pittsburgh National Supercomputing CenterMCB180091P
NIHR01GM116961
Subject Keywords:G protein-coupled receptor, sweet taste receptor, non-caloric sweetener, synergy, metadynamics
Other Numbering System:
Other Numbering System NameOther Numbering System ID
WAG1492
Issue or Number:41
DOI:10.1021/acs.jafc.1c03779
Record Number:CaltechAUTHORS:20211008-224624888
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211008-224624888
Official Citation:Synergic Effects in the Activation of the Sweet Receptor GPCR Heterodimer for Various Sweeteners Predicted Using Molecular Metadynamics Simulations. Jaewan Jang, Soo-Kyung Kim, Brian Guthrie, and William A. Goddard. Journal of Agricultural and Food Chemistry 2021 69 (41), 12250-12261; DOI: 10.1021/acs.jafc.1c03779
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111329
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:12 Oct 2021 14:07
Last Modified:08 Nov 2021 19:38

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