Synergistic Insights into Positive Allosteric Modulator and Agonist Using Gaussian Accelerated and Tau Random Acceleration Simulations in the Metabotropic Glutamate Receptor 2.

Abstract

Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. Related research shows activating metabotropic glutamate receptors holds therapeutic potential. Agonist-positive allosteric modulations (ago-PAMs) not only activate metabotropic glutamate receptors but also enhance glutamate-induced responses, offering a promising treatment strategy. However, the molecular mechanisms by which ago-PAM enhances glutamate-induced responses remain unclear, as does the potential influence of glutamate on ago-PAM. In this study, Gaussian accelerated molecular dynamics and tau random acceleration molecular dynamics simulations were employed to investigate the molecular mechanism between ago-PAM and glutamate in full-length mGlu₂. Results suggest that the ago-PAM JNJ-46281222 enhances the binding affinity and residence time of glutamates in the Venus flytrap (VFT) domains by initiating a variant reverse communication from the heptahelical transmembrane (7TM) domains to VFTs via the cysteine-rich domains. Meanwhile, glutamate facilitates the interaction between Trp676 and Glu701 to further induce the relaxation of TM5, promoting the opening of the PAM-binding pocket. Glutamate can also promote the upward rotation of the cyclopropylmethyl group of the JNJ-46281222 to bring the TM6-TM6 distance closer. Nevertheless, it remains uncertain how the binding between mGlu₂ and G protein differs when induced by small molecules binding in allosteric sites, orthosteric sites, or both. In conclusion, this study shed new light on the positive coordination relationship between ago-PAM and glutamate in the full-length mGlu₂ receptor, which could help develop novel and more effective ago-PAM to treat schizophrenia.