Estimation of Ligand Efficacies of Metabotropic Glutamate Receptors from Conformational Forces Obtained from Molecular Dynamics Simulations

Abstract

Group 1 metabotropic glutamate receptors (mGluR) are G-protein coupled receptors with a large bilobate extracellular ligand binding region (LBR) that resembles a Venus fly trap. Closing of this LBR in the presence of a ligand is associated with the activation of the receptor. From conformational sampling of the LBR-ligand complexes using all-atom molecular dynamics (MD) simulations, we characterized the conformational minima related to the hinge like motion associated with the LBR closing/opening in the presence of known agonists and antagonists. By applying a harmonic restraint on the LBR, we also determined the conformational forces generated by the different ligands. The change in the location of the minima and the conformational forces were used to quantify the efficacies of the ligands. This analysis shows that efficacies can be estimated from the forces of a single conformation of the receptor, indicating the potential of MD simulations as an efficient and useful technique to quantify efficacies thereby facilitating the rational design of mGluR agonists and antagonists.

DIRECT‐ID: An automated method to identify and quantify conformational variations—application to β2‐adrenergic GPCR

“…Molecular dynamics (MD) simulations are extremely powerful towards this understanding in that they provide high‐resolution details of spatial arrangement of particles in a system over time. Atomistic MD simulations spanning a wide range of time‐scales have been employed extensively in the past to understand different aspects of dynamics and functions of biomacromolecules of different sizes . However, the overwhelming amount of information in MD trajectories detailing the time‐evolution of the system is often under‐utilized .…”

“…Atomistic MD simulations spanning a wide range of timescales have been employed extensively in the past to understand different aspects of dynamics and functions of biomacromolecules of different sizes. [2][3][4][5] However, the overwhelming amount of information in MD trajectories detailing the timeevolution of the system is often under-utilized. [6] Thus, it is beneficial to refine analysis methods to optimize the extraction of functionally relevant conformational information.…”

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

“…either amino acids or cyclotryptophan/TNCA) at the hinge region (Site 1) of the ECD and the highly negatively charged dimerization site (Site 2) between two CaSR protomers (Figure 3B ). 105 , 111 This is also observed with other closely related class C GPCRs, such as mGluRs, which sense the amino acid glutamate and [Ca 2+ ] o via binding pockets in the ECD, 133 and in the GABA B Rs, which sense an important glutamic acid decarboxylase (GAD)‐dependent metabolite of glutamate, known asγ‐aminobutyric acid, or GABA. 134 Upon binding of Ca 2+ and amino acid/TNCA to the hinge region, Ca 2+ then binds to the acidic homodimer interface of VFT Lobe 2, inducing conformational changes at CRD and the TMD with movement of TM6 and possibly the C‐terminal tail.…”

Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5

“…Although numerous orthosteric mGluR5 agonists are known, 17–20 none have been used in the clinic largely due to the challenge in identifying selective 21 and CNS permeable agonists of the receptor. Recent advances in the development of positive allosteric modulators (PAMs), by targeting the seven-helical trans-membrane (TM) of mGluR5, have provided new opportunities for discovery of therapeutic agents for TBI.…”