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

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 (Δ g inter ) 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.