Exploring GPR109A Receptor Interaction with Hippuric Acid Using MD Simulations and CD Spectroscopy

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Phenolic acids (PAs), gut microflora metabolites, promote bone development and prevent degeneration.
• G-protein-coupled receptor 109A (GPR109A) acts as a receptor for PAs like hippuric acid (HA).
• HA shares structural similarities with niacin, a known GPR109A ligand, but binding details are unclear.

Purpose of the Study:

• To elucidate the molecular determinants of hippuric acid (HA) binding to GPR109A and GPR109B.
• To understand the role of these interactions in regulating osteoclastogenesis.
• To investigate the binding mechanism and affinity of HA to GPR109A/B.

Main Methods:

• Computational docking and molecular dynamics simulations were used to model HA binding.
• Homology models of GPR109A and GPR109B were employed.
• Molecular Mechanics Poisson-Boltzmann solvent accessible area (MM-PBSA) calculations and in silico mutation analysis were performed.
• Time-resolved circular dichroism spectroscopy was used to assess protein conformational changes.

Main Results:

• HA binds to GPR109A similarly to niacin, involving specific transmembrane helices and extracellular loop residues.
• HA exhibits higher binding affinity for GPR109A than for GPR109B.
• In silico mutations of key residues disrupted HA binding to GPR109A.
• No significant changes in protein secondary structure were observed upon HA binding.

Conclusions:

• A detailed mechanism for HA interaction with GPR109A and GPR109B receptors is proposed.
• Specific residues in GPR109A and GPR109B are critical for HA binding.
• These findings contribute to understanding how gut metabolites influence bone health via GPR109A signaling.