Multiscale simulations on human Frizzled and Taste2 GPCRs

Area of Science:

• Biochemistry and Molecular Biology
• Structural Biology
• Pharmacology

Background:

• G protein-coupled receptors (GPCRs) are crucial cell surface receptors involved in numerous physiological processes.
• Class F GPCRs, including Frizzled and Taste2 receptors, represent a distinct subfamily with unique structural and functional properties.
• Understanding the molecular mechanisms of Class F GPCRs is essential for developing targeted therapeutics.

Purpose of the Study:

• To elucidate the functional mechanisms of Class F GPCRs using advanced computational methods.
• To investigate the structural basis for activation and drug binding in specific Class F GPCRs.
• To explore the molecular determinants of ligand recognition in Taste2 receptors.

Main Methods:

• All-atom, coarse-grained, and hybrid molecular dynamics (MD) simulations were employed.
• Simulations were performed on various Class F GPCRs, including FZD4 and Smoothened.
• Computational analysis focused on receptor activation, drug binding, and ligand recognition.

Main Results:

• Frizzled receptor FZD4 activation involves a significant bending of transmembrane helix TM7, distinct from Class A GPCRs.
• A drug-resistant Smoothened receptor variant exhibits reduced drug affinity due to mutations affecting the binding cavity and TM6.
• A novel two-state recognition mechanism was identified for the Taste2 receptor hTAS2R46, explaining its broad agonist diversity.

Conclusions:

• Molecular dynamics simulations provide valuable insights into the complex functional mechanisms of Class F GPCRs.
• These findings highlight the structural plasticity and diverse activation pathways within the Frizzled and Taste2 receptor families.
• The study offers a molecular basis for understanding drug resistance and ligand recognition, potentially guiding future drug design for GPCR targets.