Dynamical Mechanisms of Glutamate Receptor Gating and Sub-Conductance

Abstract

Ionotropic glutamate receptors (iGluR) are responsible for initiation of excitatory signal transmission in the central nervous system (CNS). They play important roles in synaptic plasticity and long-term potentiation, while their dysfunction causes variety of diseases including neurodegenerative diseases and epilepsy, therefore they are potential targets for drug design. Glutamate receptors exhibit a distinctly modular multi-domain structure, in which truncated proteins containing only the ligand binding domain (LBD) and the transmembrane domains (TM) form the smallest functional glutamate gated channels. These homo-tetrameric AMPA subtype glutamate receptors gating and desensitization occurs on millisecond time-scales, and thus, these are the smallest and fastest working ligand-gated ion channels. In this work we report on extensive multy-microsecond molecular dynamics (MD) simulations of the AMPA receptor gating and regulation. The simulations were designed to allow the receptors to inter-convert between their various functional states, such as open and closed TM channel, and ligand-bound, active and desensitized LBD domain. We have used a variety of machine learning (ML) methods and systematic feature selection techniques to characterize which specific features of the LBD structure are responsible for transducing the signal for channel opening. We have observed multiple events of partial closures of the channel correlated with the LBD cleft closure degree from which we are able to draw conclusions on specific mechanism of allosteric coupling between the LBD domains monomeric and quarternary structures, as well as the ion channel state of the TM domains. Our study is the first one that was able to successfully design a simulation for opening and closing of the TM ion channel in response to the state of the LBD domain and characterize thus far elusive sub-conductance states.