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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.

Existing optogenetic tools for controlling protein-protein interactions are available in a limited number of wavelengths thereby limiting opportunities for multiplexing. The cyanobacteriochrome (CBCR) family of photoreceptors responds to an extraordinary range of colors, but light-dependent binding partners for CBCR domains are not currently known. We used a phage-display based approach to develop small (~50-residue) monomeric binders selective for the green absorbing state (Pg), or for the red absorbing state (Pr) of the CBCR Am1_c0023g2 with a phycocyanobilin chromophore and also for the far-red absorbing state (Pfr) of Am1_c0023g2 with a biliverdin chromophore. These bind in a 1:1 mole ratio with KDs for the target state from 0.2 to 2 μM and selectivities from 10 to 500-fold. We demonstrate green, orange, red, and far-red light-dependent control of protein-protein interactions in vitro and also in vivo where these multicolor optogenetic tools are used to control transcription in yeast.