Theoretical studies of ligand-receptor interactions in sodium and calcium channels

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Sodium (Na) and calcium (Ca) channels play key roles in physiology of muscle and nerves. They are targets for various drugs and toxins (ligands). Cryo-electron microscopy (cryo-EM) structures of several Na and Ca channels with ligands are available, but for most of ligands atomic mechanisms remain unclear. Besides, ligand-channel interactions in deeply frozen protein samples and in living cells may differ. Computer-based modeling employing data from decades of experimental studies can be used to understand ligands' atomic mechanisms at physiological conditions. Towards this goal I propose the following program. Ca channel with cardiovascular drugs. Surprisingly, in cryo-EM structures dihydropyridines (DHPs) are far from the Ca permeation pathway and from several DHP-sensing residues whose mutations affect DHP action. Furthermore, the channel geometry with DHPs that either facilitate or block Ca current is the same. We will explore an intriguing possibility that DHPs and DHP-sensing residues affect Ca current by perturbing Ca hydration shell that is invisible in cryo-EM. Paradoxically, some cationic and electroneutral ligands target the same sites in ion channels. Earlier we proposed that cationic ligands displace Na, Ca or K and bind at their sites, while Na, Ca or K attract ligands' electronegative atoms. This mechanism is now shown for K channels, but for Na or Ca channels it is still a hypothesis. In our models verapamil binds to a Ca ion in the channel selectivity filter, but in a cryo-EM structure such contact is obstructed by a detergent molecule, which is absent in the living cell. We will dock verapamil and electroneutral ligands to the Ca channel to explore ligand-ion interactions and explain intriguing paradoxes in the ligands' structure-activity relations. Ca channel with conotoxins. Conotoxin peptides produced by marine cone snails selectivity block specific Ca channels. Intriguingly, both cationic and anionic conotoxins target the same Ca channel subtype. We will dock these conotoxins in the channel to test a hypothesis that anionic toxins bind to Ca ions in the pore, whereas cationic conotoxins displace Ca ions and bind to their sites. Na channels with ligands. The pore of Na channels is targeted by ligands of intriguingly different structure. We will model Na channel complexes with some drugs and toxins. We collaborate with Dr. Ke Dong (USA) to study action of insecticides on insect Na channels and understand how insects adapt to insecticides. We will continue this productive collaboration. We use the ZMM program, which I have created, as a principal (but not the only) computational tool. ZMM success rate in predicting ligand-protein complexes is not lower than that of better known programs. We keep adapting ZMM in-house to address computational problems of ever increasing complexity. Our studies will advance the knowledge on neuron and muscle cells regulation by ligands and assist in structure-based drug design.