Abstract

Ion channels regulate the permeation of ions across cell membranes through the reception of electrical and chemical stimuli, thereby playing an essential physiological role in neural transmission, heartbeat, and muscle contraction. Mutations in ion channels result in pathologies such as hypersensitivity to pain, long QT syndrome, and epilepsy. High-resolution structures of small molecules in complex with ion channels has allowed computational biologists to hypothesize and test molecular mechanisms of ion channel gating. Rosetta's GALigandDock, a new ligand docking approach, uses a genetic algorithm to effectively sample the ligand-receptor energy landscape to predict structural conformations. Here, we present initial benchmarking results of Rosetta's GALigandDock with several classes of voltage-gated ion channels. Preliminary results indicate that GALigandDock is able to successfully dock Protein Data Bank deposited small molecules to their experimentally resolved binding sites, such as the fenestration region of the voltage-gated sodium and calcium channels. GALigandDock is also able to determine low-energy regions of binding not documented in the Protein Data Bank, providing structural hypotheses for further testing. The use of GALigandDock in further tests will provide a basis for rational design of novel small molecules targeting ion channels with high potency and selectivity.

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