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

TY - JOUR

T1 - Mutagenesis Computer Experiments in Pentameric Ligand-Gated Ion Channels: the Role of Simulation Tools with Different Resolution

AU - Crnjar, Alessandro

AU - Comitani, Federico

AU - Melis, Claudio

AU - Molteni, Carla

PY - 2019/4/19

Y1 - 2019/4/19

N2 - 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.

AB - 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.

KW - Enhanced sampling methods

KW - First principles methods

KW - Metadynamics

KW - Molecular dynamics

KW - Mutagenesis electrophysiology experiments

KW - Pentameric ligand-gated ion channels

UR - http://www.scopus.com/inward/record.url?scp=85065341736&partnerID=8YFLogxK

U2 - 10.1098/rsfs.2018.0067

DO - 10.1098/rsfs.2018.0067

M3 - Review article

SN - 2042-8898

VL - 9

JO - Interface Focus

JF - Interface Focus

IS - 3

M1 - 20180067

ER -