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

Area of Science:

• Biochemistry and Molecular Biology
• Computational Chemistry
• Sensory Science

Background:

• Sweet taste perception is mediated by the T1R2-T1R3 sweet taste receptor (STR).
• The precise interactions between STR and sweeteners remain incompletely understood.
• Understanding these interactions is crucial for developing novel sweetening agents.

Purpose of the Study:

• To elucidate the key noncovalent interactions between the T1R2 Venus flytrap domain (VFD) and aspartame in its active conformation.
• To establish a computational methodology for quantifying ligand-protein interactions in the STR system.
• To provide a basis for the rational design of new sweeteners through structural modifications of aspartame.

Main Methods:

• Coupling molecular dynamics (MD) simulations with the independent gradient model (igm) approach (MD-igm).
• Quantifying noncovalent interactions using the Δg inter score based on electronic density gradient attenuation.
• Analyzing ligand-cavity contacts and inter-residue interactions stabilizing the VFD closed form.
• Applying atomic decomposition to assess the contribution of aspartame segments to binding.

Main Results:

• Detailed identification of the main interacting signatures between aspartame and the T1R2 VFD.
• Quantification of noncovalent interactions and their contribution to STR-ligand binding.
• Characterization of residue-level interactions critical for VFD stability in the presence of aspartame.

Conclusions:

• The MD-igm approach offers a rapid and reliable method for quantifying noncovalent interactions in biomolecular systems.
• This methodology provides valuable insights into sweet taste receptor-ligand dynamics.
• The findings offer guidelines for the rational design of novel sweeteners with improved properties.