BPS2026 – Modeling structure informed function in tetrameric ion channels

Tetrameric bundles of transmembrane alpha helical assemblies are a common topology for ion channels in biological membranes. We will present computational studies of two classes of such channels: the ionotropic glutamate receptors (iGluRs), which are found in the central nervous system (CNS) and initiate transmission of signal in excitatory synapses; and the transient receptor proteins (TRPs), a class of ubiquitous ion channels regulated by multiple stimuli, including temperature, pressure and ligands, which are selective to divalent cations. Proteins of both classes are essential for function and present attractive pharmaceutical targets. Detailed understanding of structure-function relationships in such proteins has been a subject of active research, yet it is difficult to connect structural information with physiological findings. We employed a combination of theoretical and computational approaches, including molecular dynamics (MD) simulations, free-energy methods, and machine learning (ML) techniques to deduce structural and dynamic variability in the structural ensembles of some members of these protein classes, to predict ion conductance and selectivity, as well as to analyze their interaction with the drug-like ligands.