Emergence of sweet ligand-protein complexes from seemingly non-sweet conformations

:Abstract

Sweet taste perception starts from the interaction of a sweet molecule with residues of the sweet taste receptor (STR). Yet, how the perception of sweet taste emerges from this interaction is still not clear. Here, we reveal a potential mechanism in the initial stages of this cascade. In our previous studies, we observed a 0.6 Pearson correlation coefficient between binding affinity and sweetness intensity. We conducted a series of MD simulations by YASARA Structure, for a total of 1.8 microseconds, to further investigate the mechanism of action of the molecules which we observed to induce considerable sweet taste perception despite having low binding affinity. We observed a gradual expansion in the hydrogen bond (HBond) network around each sweetener in the binding site which involved the water molecules and the residues of the binding pocket. Important HBond and hydrophobic interactions for sweet taste were detected. Some of the residues which we identified to be involved in the HBond network, and also to cause pattern changes in the dynamic cross-correlation matrix, have been known to be parts of the sweet taste signaling pathway. An analysis of the sweeteners' pharmacophore during the MD experiments demonstrated a gradual emergence of the Nofre-Tinti conformation, a proposed determinant in the sweetness intensity, in the ligands despite its initial absence in the ligand–protein complex. In conclusion, these results reveal a novel mechanism for inducing sweet taste and open a new avenue for designing artificial sweeteners, besides the classical hunt for high binding affinity