Revisiting the Sweet Taste Receptor T1R2-T1R3 through Molecular Dynamics Simulations Coupled with a Noncovalent Interactions

It is nowadays widely accepted that sweet taste perception is elicited by the activation of the heterodimeric complex T1R2-T1R3, customarily known as sweet taste receptor (STR). However, the interplay between STR and sweeteners has not yet been fully clarified. Here through a methodology coupling molecular dynamics and the independent gradient model (igm) approach we determine the main interacting signatures of the closed (active) conformation of the T1R2 Venus flytrap domain (VFD) toward aspartame. The igm methodology provides a rapid and reliable quantification of noncovalent interactions through a score (Delta ginter) based on the attenuation of the electronic density gradient when two molecular fragments approach each other. Herein, this approach is coupled to a 100 ns molecular dynamics simulation (MD-igm) to explore the ligand-cavity contacts on a per-residue basis as well as a series of key inter-residue interactions that stabilize the closed form of VFD. We also apply an atomic decomposition scheme of noncovalent interactions to quantify the contribution of the ligand segments to the noncovalent interplay. Finally, a series of structural modification on aspartame are conducted in order to obtain guidelines for the rational design of novel sweeteners. Given that innovative methodologies to reliably quantify the extent of ligand-protein coupling are strongly demanded, this approach combining a noncovalent analysis and MD simulations represents a valuable contribution, that can be easily applied to other relevant biomolecular systems.

Automated summary

It is widely accepted that sweet taste perception is activated by the sweet taste receptor (STR), a complex of T1R2 and T1R3. However, the interaction between STR and sweeteners is not fully understood. In this study, a combination of molecular dynamics and the independent gradient model (igm) approach was used to analyze the interaction between the T1R2 Venus flytrap domain (VFD) and aspartame. The results provide insights into the key interactions that stabilize the closed form of VFD and can be applied to the design of new sweeteners.