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Kinetic Modeling of Glutamate Receptor Ion Channels

Creative Bioarray is committed to helping clients analyze the gating motions and stationary gating characteristics of iGluRs through molecular dynamics (MD) simulation and theoretical modeling technology, contributing to filling some knowledge gaps in the structure and function of iGluRs.

Introduction

AMPARs and NMDARs are the two major subtypes of postsynaptic iGluRs, which are responsible for initiating excitatory signaling in the central nervous system (CNS). These receptors convert transient glutamate signals generated by presynaptic release into postsynaptic electrical and biochemical signals. The strength of synaptic connections between neurons depends on the duration of glutamate-induced channel opening, which is critical for neural development and higher-order processes such as memory.

Due to their physiological importance and pathophysiological significance, iGluRs have received extensive attention from researchers. The determination of isolated domains and transmembrane-domain-containing structures provides a basis for formulating mechanistic hypotheses. However, these structures represent only sparse and incomplete snapshots during iGluR activation, and the structural, energetic, and kinetic aspects of key substates during functional processes remain unknown. The development of MD simulation techniques has opened up the possibility of connecting the two conformational snapshots through physically plausible pathways, allowing the exploration of the molecular motions of iGluRs from one functional state to another.

Theoretical model for iGluR gating thermodynamics and kinetics.Fig. 1 Theoretical model for iGluR gating thermodynamics and kinetics. (Zhou, 2017)

Our Services

We are dedicated to helping our clients through MD simulations to analyze the transition of receptors between their various functional states, such as open and closed TM channels, as well as ligand binding, activity and desensitized LBD domains. In addition, we combine MD simulation technology with computing and electrophysiology to explore the thermodynamic and dynamic characteristics of gating processes. Our services include but not limited to:

  • Simulations of gating motions
    We have successfully helped our clients develop an activation model in which the M3-D2 linker plays important and subunit-specific roles based on MD simulations. In addition, we combine single-channel recordings, computational, and electrophysiological techniques to delve into the mechanical coupling between the LBDs and TMD tetramer by the linkers.
  • Free energy simulations
    We use free energy simulations to help our clients explore the conformational space of proteins. We establish free energy models of the full receptor to provide the theoretical basis for the mechanistic hypothesis on partial agonisms.
  • Theoretical modeling
    We help clients model free energy functions of the full receptors based on mechanistic insights about channel activation gained from our target MD simulations. In addition to thermodynamic properties, our model extends to stationary gating dynamics.

Applications

  • Research on the conformations of key substates in functional processes
  • Study on NMDAR physiology and pathophysiology
  • Study on the mechanisms of disease-associated mutations

Creative Bioarray has established a variety of technologies to provide clients with MD simulation of the iGluR gating process to predict the functional characteristics of iGluR from intra- and interdomain energetics and dynamics in MD simulations. If you are interested in our services, please contact us for more details.

Reference

  1. Zhou, H. X. Gating motions and stationary gating properties of ionotropic glutamate receptors: Computation meets electrophysiology. Accounts of chemical research, 2017, 50(4): 814-822.
For Research Use Only.