Computational approaches exploring the structure and dynamics of ligand-gated ion channel receptors.

Abstract

This thesis explores ligand-gated ion channels including the N-methyl-D-asparate (NMDA) and P2X7 receptors. They are crucial in physiological processes and diseases like epilepsy, cancer, Alzheimer's disease, and inflammation. These ion channels, composed of multiple subunits, change conformation upon ligand binding, allowing ion flux, affecting cell polarisation, and influencing downstream messengers or cell death. Challenges in determining their structures and actions make drug design difficult.

Advancements in computational methods such as molecular dynamics, homology modelling, AlphaFold2, and cryogenic electron microscopy have enabled in-depth studies of these channels. Specifically, the thesis investigates the N-methyl-D-aspartate receptor, a tetrameric channel requiring specific ligand binding for activation. The Ser688Tyr mutation within this receptor reduces response to glycine ligands, impacting binding affinity, as shown through simulations and calculations.

The thesis also examines P2X7 receptors, trimeric channels activated by ATP, involved in inflammation and cell death. Cholesterol's interaction with these receptors, modulating activation, is studied using molecular dynamics simulations. Alternative splicing of P2X7 receptors, leading to impaired variants, is another focus area, using AlphaFold2 for structural predictions and exploring optimal linker lengths for receptor concatenation.

Overall, the research demonstrates the utility of computational modelling in understanding ligand-gated ion channels, aiding interpretation of in vitro data, and guiding future studies and drug discovery.