Molecular Modeling in Studies of Ion Channels and their Modulation by Ligands

Ion channels constitute a diverse family of transmembrane proteins, which regulate flow of ions through cell membranes. The channels are involved in multiple physiological processes and they are targets for numerous naturally occurring toxins and medically important drugs. However, molecular details of the channel structure, mechanisms of action, and interaction with ligands are still debated. A reason for this is the shortage of atomic-level three dimensional structures. During last two decades significant contributions to the field have been made with indirect experimental approaches including mutagenesis, electrophysiology, and analysis of structure-function relations. Molecular modeling was applied to rationalize these experimental data in structural terms. Recent achievements of the x-ray crystallography and cryo-electron microscopy provide unambiguous solutions for many structural problems that were previously addressed by indirect and modeling studies. In this review we describe several examples of structural predictions that have been made by molecular modeling with the aim to rationalize indirect experimental data. We compare the models with recently published crystal and cryo-EM structures. A good agreement of many predictions with the later published experimental structures validates further employment of molecular modeling studies. Currently available and expected structures of principal ion channels and their complexes with ligands provide realistic templates for modeling homologous channels, their multiple variants, including decease-associated mutants, and docking drugs and toxins in the models. These studies are expected to provide high-quality predictions, which are necessary to design new channel-specific ligands and provide recommendations for personalized chemotherapy.