Metadynamics-Based Mechanistic Interpretation of Functional Crosstalk Between Serotonin 2A and Metabotropic Glutamate 2 receptors

Abstract

Serotonin 2A (2AR) and metabotropic glutamate 2 (mGluR2) receptors have been shown to form a functional and specific heteromeric complex in mammalian brain and in tissue culture preparations with possible implications in the psychotic symptoms of schizophrenia. Unlike non-antipsychotic drugs, clinically effective atypical antipsychotics (e.g., clozapine) that bind to 2AR increase the glutamate-mediated Gi signaling through the 2AR/mGluR2 heterodimer. The molecular mechanisms underlying these allosteric effects and functional crosstalk are unknown. Using molecular dynamics (MD) simulations enhanced with metadynamics, we investigated at the molecular level the conformational changes induced by atypical antipsychotic or non-antipsychotic 2AR ligands in atomistic representations of interacting 2AR and mGluR2 embedded in an explicit lipid-water environment. First, we sampled the conformational transitions from inactive to activated (opsin-like) models of the ligand-free transmembrane regions of 2AR or mGluR2 with adiabatic biased MD simulations. We then reconstructed the free-energy landscape of the 2AR/mGluR2 heterodimer along the pre-determined transition trajectories in the presence of ligands, using a path collective variable approach based on metadynamics. The CHARMM force-field with the CMAP backbone energy correction was used to describe the full systems. All calculations were performed using NAMD enhanced with the Plumed plug-in. Our results suggest that the conformational transitions of 2AR and mGluR2 are populated by different inactive and active metastable states of the receptors, which are differentially stabilized by antipsychotic and non-antipsychotic ligands.