Phenylalkylamines in calcium channels: computational analysis of experimental structures
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Phenylalkylamines in calcium channels: computational analysis of experimental structures Denis B. Tikhonov1 · Lianyun Lin2 · Daniel S. C. Yang3 · Zhiguang Yuchi2 · Boris S. Zhorov1,3,4 Received: 31 January 2020 / Accepted: 3 July 2020 © Springer Nature Switzerland AG 2020
Abstract Experimental 3D structures of calcium channels with phenylalkylamines (PAAs) provide basis for further analysis of atomic mechanisms of these important cardiovascular drugs. In the crystal structure of the engineered calcium channel CavAb with Br-verapamil and in the cryo-EM structure of the Cav1.1 channel with verapamil, the ligands bind in the inner pore. However, there are significant differences between these structures. In the crystal structure the ligand ammonium group is much closer to the ion in the selectivity-filter region Site 3, which is most proximal to the inner pore, than in the cryo-EM structure. Here we used Monte Carlo energy minimizations to dock PAAs in calcium channels. Our computations suggest that in the crystal structure Site 3 is occupied by a water molecule rather than by a calcium ion. Analysis of the published electron density map does not rule out this possibility. In the cryo-EM structures the ammonium group of verapamil is shifted from the calcium ion in Site 3 either along the pore axis, towards the cytoplasm or away from the axis. Our unbiased docking reproduced these binding modes. However, in the cryo-EM structures detergent and lipid molecules interact with verapamil. When we removed these molecules, the nitrile group of verapamil bound to the calcium ion in Site 3. Models of Cav1.2 with different PAAs suggest similar binding modes and direct contacts of the ligands electronegative atoms with the calcium ion in Site 3. Such interactions explain paradoxes in structure–activity relationships of PAAs. Keywords Verapamil · Phenylalkylamines · Calcium · X-ray crystallography · Cryo electron microscopy · Monte carlo energy minimizations Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00330-0) contains supplementary material, which is available to authorized users. * Denis B. Tikhonov [email protected] * Zhiguang Yuchi [email protected] * Boris S. Zhorov [email protected] 1
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russian Federation
2
Tianjin Key Laboratory for Modern Drug Delivery & High‑Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
3
Almazov National Medical Research Centre, St. Petersburg, Russia 197341
4
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
Abbreviations BrVp Br-verapamil MC Monte Carlo MCM MC-minimizations PAA Phenylalkylamine RMS Root Mean Square
Introduction Voltage-gated calcium channels play fundamental roles in physiology [1]. Their ligands are used as medically im
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