Mutagenesis Computer Experiments in Pentameric Ligand-Gated Ion Channels: the Role of Simulation Tools with Different Resolution

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Abstract

Pentameric ligand-gated ion channels are an important class of widely expressed membrane neuroreceptors, which play a crucial role in fast synaptic communications and are involved in several neurological conditions. They are activated by the binding of neurotransmitters, which trigger the transmission of an electrical signal via facilitated ion-flux. They can also be activated, inhibited or modulated by a number of drugs. Mutagenesis electrophysiology experiments, with natural or unnatural amino acids, have provided a large body of functional data that, together with emerging structural information from X-ray spectroscopy and cryo-electron microscopy, are helping unravel the complex working mechanisms of these neuroreceptors. Computer simulations are complementing these mutagenesis experiments, with insights at various levels of accuracy and resolution. Here we review how a selection of computational tools, including first principles methods, classical molecular dynamics and enhanced sampling techniques, are contributing to construct a picture of how pentameric ligand-gated ion channels function and can be pharmacologically targeted to treat the disorders they are responsible for.
Original languageEnglish
Article number20180067
JournalInterface Focus
Volume9
Issue number3
DOIs
Publication statusPublished - 19 Apr 2019

Keywords

  • Enhanced sampling methods
  • First principles methods
  • Metadynamics
  • Molecular dynamics
  • Mutagenesis electrophysiology experiments
  • Pentameric ligand-gated ion channels

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