Modeling L-type Calcium Channel with Dihydropyridines

Abstract

Dyhydropyridines (DHPs) is a major class of L-type calcium channel (LCC) ligands, which have boat-like six-membered ring with NH-group at the stern, aromatic moiety at the bow, and various substituents at the port and starboard sides. DHPs demonstrate antagonistic or agonistic action, which was previously explained as stabilization or destabilization, respectively, of the closed-gate state by the hydrophilic or hydrophobic port-side substituent. Here we used Monte Carlo energy-minimizations to dock various DHPs in the open-LCC model (Tikhonov & Zhorov, 2008). The calculations suggest a novel structural model in which agonistic and antagonistic actions are determined by different parts of the DHP molecule and have different molecular mechanisms. In our model, DHP polar moieties at the stern, bow, and starboard form H-bonds with side chains of Tyr_IVS6, Tyr_IIIS6, and Gln_IIIS5, respectively. The aromatic moiety at the bow binds to Phe_IIIP. We propose that these contacts with the well-known DHP-sensing residues stabilize the channel's open-gate conformation. Since these contacts are common for various DHPs, our model explains why both agonist and antagonists increase probability of the long-lasting channel openings and why even partial disruption of the contacts eliminates the agonistic action. In our model, the port-side is exposed to the permeation pathway and approaches the selectivity filter. Hydrophobic ports-side group of antagonists may induce long-lasting channel closings by destabilizing calcium coordination with the selectivity-filter glutamates in domains III and IV. In contrast, agonists, which have either hydrophilic or no substituent at the port-side, lack this destabilizing effect. Our model explains action of DHPs with diverse substituents. Thus, long substituents at the port-side are readily accommodated in the pore. Long substituents at the starboard-side protrude in the III/IV domain interface, explaining activity of DHPs linked to a permanently charged group. Supported by CIHR.