MD Simulation of Conformational Changes of pLGICs

Creative Bioarray is committed to providing clients with molecular dynamics simulations of pLGIC conformational transitions to elucidate the structural basis of pLGIC functions. We combined structural, functional, and computational approaches to help our clients obtain high-quality structural templates in multiple functional states, providing useful information for a detailed understanding of the biophysics and pharmacology of pLGICs.

Introduction

pLGICs are a major family of neurotransmitter receptors, and elucidating the structural basis of the functions of these channels in detail is one of the important topics for neuroscientists and biophysicists. The recent proliferation of crystal structures of pLGICs has driven research on the atomic basis of their functional properties. However, the crystal structures only provide static pictures and fail to capture the conformational changes that pLGICs undergo from a closed to an open state to a desensitized state. Developments in molecular dynamics have provided powerful tools for understanding the transitions of these channels between functional states at the atomic level.

pLGICs have at least three functional states, including a closed state in the absence of agonist (the resting non-conducting state) and two activated states in the presence of agonist (the open conducting state and the desensitized non-conducting state). Of these, the absence of regulatory ligands has rarely been reported, and the resting-state structural and kinetic properties have not been elucidated. Therefore, it is necessary to combine molecular dynamics simulations to reveal the structural basis for the function of pLGICs and fundamental properties to employ them e.g. for drug design.

Fig. 1 A dynamic resting state of pentameric ligand-gated ion channels. (Rovšnik, 2020)

Our Services

Combining the wealth of structural information available about pLGICs, our researchers use molecular dynamics simulations to help clients explore the dynamic properties of pLGICs. Our services include but not limited to:

• Analysis of pore opening and closing of pLGICs.
  We have successfully helped our clients study the gating transition of pLGIC by constructing a transition pathway between the open and closed structures of the GLIC transmembrane domain (TMD).
• Analysis of ion conductance in open and closed states
• Simulation of the closing transition of GLIC pore
• Analysis of gating energetics, such as thermodynamic and kinetic analysis of pore closing
• Simulation of the dynamic resting state of pLGICs.
• Modeling of Cryo-EM structures of closed GLIC
• Analysis of local rearrangements associated with protonation
• Analysis of flexibility of the resting-state extracellular domain (ECD)
• Analysis of conformational coupling between ECD and TMD.

Applications

• Research on pLGICs functions
• Research on the structural basis and the gating processes for function in pLGICs
• Research on intramolecular signal transduction mechanism of pLGICs

Creative Bioarray is committed to establishing a variety of technologies to provide clients with molecular dynamics simulation of conformational transformation of pLGICs, providing new insights into the molecular mechanism of gating and allosteric regulation. Our powerful techniques provide novel opportunities to explore the ligand regulation in this important neurotransmitter receptor family. If you are interested in our services, please contact us for more details.

Reference

1. Rovšnik, U.; et al. Characterization of the dynamic resting state of a pentameric ligand-gated ion channel by cryo-electron microscopy and simulations. bioRxiv, 2020.