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Seeking the exclusive binding region of phenylalkylamine derivatives on human T-type calcium channels via homology modeling and molecular dynamics simulation approach.

ABSTRACT: Pharmaceutical features of phenylalkylamine derivatives (PAAs) binding to calcium channels have been studied extensively in the past decades. Only a few PAAs have the binding specificity on calcium channels, for example, NNC 55-0396. Here, we created the homology models of human Ca_v 3.2, Ca_v 3.3 and use them as a receptor on the rigid docking tests. The nonspecific calcium channel blocker mibefradil showed inconsistent docking preference across four domains; however, NNC 55-0396 had a unique binding pattern on domain II specifically. The subsequent molecular dynamics (MD) simulations identified that Ca_v 3.1, Ca_v 3.2, and Ca_v 3.3 share domain II when Ca²⁺ appearing in the neighbor region of selective filters (SFs). Moreover, free-energy perturbation analysis suggests single mutation of lysine at P-loop domain III, or threonine at the P-loop domain II largely reduced the total amount of hydration-free energy in the system. All these findings suggest that P-loop and segment six domain II in the T-type calcium channels (TCCs) are crucial for attracting the PAAs with specificity as the antagonist.

SUBMITTER: Lu Y

PROVIDER: S-EPMC8118199 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Seeking the exclusive binding region of phenylalkylamine derivatives on human T-type calcium channels via homology modeling and molecular dynamics simulation approach.

Lu You Y Li Ming M Lee Gi Young GY Zhao Na N Chen Zhong Z Edwards Andrea A Zhang Kun K

Pharmacology research & perspectives 20210501 3

Pharmaceutical features of phenylalkylamine derivatives (PAAs) binding to calcium channels have been studied extensively in the past decades. Only a few PAAs have the binding specificity on calcium channels, for example, NNC 55-0396. Here, we created the homology models of human Ca<sub>v</sub> 3.2, Ca<sub>v</sub> 3.3 and use them as a receptor on the rigid docking tests. The nonspecific calcium channel blocker mibefradil showed inconsistent docking preference across four domains; however, NNC 55 ...[more]

PMID: 33984189

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Project description:HCN channels are activated by membrane hyperpolarization and regulated by cyclic nucleotides, such as cyclic adenosine-mono-phosphate (cAMP). Here we present structural models of the pore region of these channels obtained by using homology modeling and validated against spatial constraints derived from electrophysiological experiments. For the construction of the models we make two major assumptions, justified by electrophysiological observations: i), in the closed state, the topology of the inner pore of HCN channels is similar to that of K(+) channels. In particular, the orientation of the S5 and S6 helices of HCN channels is very similar to that of the corresponding helices of the K(+) KcsA and K(+) KirBac1.1 channels. Thus, we use as templates the x-ray structure of these K(+) channels. ii), In the open state, the S6 helix is bent further than it is in the closed state, as suggested (but not proven) by experimental data. For this reason, the template of the open conformation is the x-ray structure of the MthK channel. The structural models of the closed state turn out to be consistent with all the available electrophysiological data. The model of the open state turned out to be consistent with all the available electrophysiological data in the filter region, including additional experimental data performed in this work. However, it required the introduction of an appropriate, experimentally derived constraint for the S6 helix. Our modeling provides a structural framework for understanding several functional properties of HCN channels: i), the cysteine ring at the inner mouth of the pore may act as a sensor of the intracellular oxidizing/reducing conditions; ii), the bending amplitude of the S6 helix upon gating appears to be significantly smaller than that found in MthK channels; iii), the reduced ionic selectivity of HCN channels, relative to that of K(+) channels, may be caused, at least in part, by the larger flexibility of the inner pore of HCN channels.

Dataset Information

Seeking the exclusive binding region of phenylalkylamine derivatives on human T-type calcium channels via homology modeling and molecular dynamics simulation approach.

Publications

Seeking the exclusive binding region of phenylalkylamine derivatives on human T-type calcium channels via homology modeling and molecular dynamics simulation approach.

Similar Datasets

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