Identification of “on-off residues” in rat Cav1.2 α1C subunit channel using in silico analysis and docking simulation
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Author and article information
Abstract
Introduction
Voltage-dependent calcium channels (VSCC) is involved in important biological function as calcium ion transmembrane transport and cardiac contraction. VSCC is a multi-pass membrane protein, made up from α-1, α-2, β and δ subunits. α-1 subunit regulates the entry of ion calcium. Voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2 α1C subunit channel) is an isoform of VSCC, and is characterized from an high-voltage activation. Previous study have shown that class of molecules as benzothiazepines (Tikhonov D. et al, 2008), are able to block the alpha-1C subunit. Recent works have demonstrated that molecules belonged at the flavonoid class are able to inhibit or to raise channel activity (Saponara S. et al, 2011). In this work, we reported the sensing- residues that could play a key role in Cav1.2 α1C activity. Furthermore, we proposed a potential mechanism of action inside Cav1.2 α1C binding-site with differences between inhibitors and stimulants. Our work has clarifiedas the ligands operate on Cav1.2 α1C, this information could be useful in order to improve their usefulness.
Methods
The 3D structure of Cav1.2 α1C subunit channel was obtained on basis of previous work (Saponara S. et al, 2015). The structure of flavons were downloaded from Pubchem(Kim S. et al, 2015). Docking simulation was carried out through Autodock/Vina v.1.1.2 (O.Trott et al, 2010). PDBePISAwas used in order to evaluate buried surface area values (B.S.A). Protein-ligand interactions were obtained using protein–ligand interaction profiler (P.L.I.P)(Salentin S. et al, 2015). Pymol was used as molecular graphics system (The PyMOL Molecular Graphics System, Version 1.8 Schrödinger, LLC.).
Results and discussion
In vitro analysis on rat Cav1.2 L-type channel of 20 flavonoids have shown stimulatory and inhibitory activities (Saponara S. et al, 2015).The 11 inhibitors and 8 stimulators derivatives are positioned in their corresponding binding-sites with peculiar sensing-residues interactions (shown in figure 1). Analyzing the network of interactions among the two classes of flavonoids we have observed hydrogen bonds, hydrophobic interactions and π–π stacking bonds characterizing their activities that could differently promote pore open/closed conformation and decreasing voltage-sensitive calcium channel activity (Tikhonov D. et al, 2009). Furthermore, on the basis of the selectivity filters model, we have evaluated B.S.A residues values present in the binding-sites, we have observed that B.S.A of some residues dramatically decrease, showing that these residues play a key role in the pore stabilization. The different mechanism of action of these molecules can be attributed to their chemical-physical proprieties as steric hindrance and different positions of hydroxyl groups.
Cite this as
2016. Identification of “on-off residues” in rat Cav1.2 α1C subunit channel using in silico analysis and docking simulation. PeerJ Preprints 4:e2272v1 https://doi.org/10.7287/peerj.preprints.2272v1Author comment
This is an abstract which has been accepted for the BITS2016 Meeting.
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Competing Interests
The authors declare that they have no competing interests.
Author Contributions
Alfonso Trezza conceived and designed the experiments, performed the experiments, analyzed the data, wrote the paper, prepared figures and/or tables.
Andrea Bernini analyzed the data, contributed reagents/materials/analysis tools.
Ottavia Spiga analyzed the data, wrote the paper, reviewed drafts of the paper.
Data Deposition
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Funding
The authors received no funding for this work.