Voltage-gating sodium ion channel structure modeling method based on development coupling analysis

A sodium ion channel and coupling analysis technology, which is applied in the analysis of two-dimensional or three-dimensional molecular structure, electrical digital data processing, special data processing applications, etc., can solve the unresolved problems of three-dimensional structure, and overcome the poor prediction accuracy, High reliability, method reliable results

Active Publication Date: 2018-04-27
YELLOW SEA FISHERIES RES INST CHINESE ACAD OF FISHERIES SCI
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Problems solved by technology

These methods perform better in protein structure prediction with a sequence length of less than 90, however, as the sequence length increases, the conformational s

Method used

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  • Voltage-gating sodium ion channel structure modeling method based on development coupling analysis
  • Voltage-gating sodium ion channel structure modeling method based on development coupling analysis
  • Voltage-gating sodium ion channel structure modeling method based on development coupling analysis

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Embodiment 1

[0025] Embodiment 1: The structure modeling method for voltage-gated sodium ion channel of the present invention comprises the following steps:

[0026] 1) Construct four domain monomers and template structure Na respectively v Sequence alignment files between corresponding strands of PaS, such as figure 1 As shown, and using rosetta's membrane protein homology modeling method, the structure of the four domain monomers was constructed;

[0027] 2) By evolutionary coupling analysis, the interaction pairs present in the four monomers are predicted. The number of sequences that finally entered the multiple sequence alignment: DI: 1936, DII: 3923, DIII: 3390, DIV: 3597. The direct coupling analysis (DCA) value between residues in each monomer was calculated, and all residue pairs with a DCA value greater than 0.2 were retained as the final predicted interaction pair (CA_DCA).

[0028] 3) Calculate the interaction pairs within the four modeled domain monomer structures; If the ...

Embodiment 2

[0048] Example 2Na v 1.5 The interaction site with off-state local anesthetic drugs is consistent with the experimental results

[0049] 1)Na v 1.5 Complexes with off-state local anesthetics (Na v 1.5_CLA) construction

[0050] Choose to be able to Na v 1.5 Three local anesthetic molecules (CLA) acting in the off state: Pilsicainide, Bisphenol A and mexiletine as inhibitor molecules. The molecular docking method used is: use REDUCE, Autodock Tools and Autodoc4 to complete. Using CLA and Na v 1.5 A fully flexible docking method for the binding site region, using Autodock4 for docking. during the docking process. Scoring adopts the method of combining Autodock4's own scoring and Xscore scoring. Using the above method, three independent dockings were carried out for each drug molecule, and finally 57, 63 and 110 complex conformations were generated for the molecules of picicanilide, polyphenol A and mecillin, respectively. Select the molecular conformation with the lowes...

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Abstract

The invention relates to a voltage-gating sodium ion channel structure modeling method based on development coupling analysis, and belongs to the field of structural biology. The method includes the steps that through the rosetta membrane-protein homology modeling method, a eukaryon sodium ion channel NavPas (PDBid:5X0M) tertiary structure serves as a template, and four subunit structures of whicha Nav1.5 pore domain is composed are primarily established; through the development coupling analysis (DCA) method, the contact ratio between actual residue pairs and interaction residue pairs obtained after forecasting through DCA in the structures is evaluated; combined with a scoring function, the structures with the high score and the high contact ratio are selected as initiating structures of all structural domains; the four selected subunit structures are assembled and optimized; a structure capable of having the high interface contact ratio and the high RosettaMP score to meet the evaluation requirements is further selected from the optimized structures to serve as a final structure. According to the voltage-gating sodium ion channel structure modeling method based on development coupling analysis, the defects that in a traditional structure modeling method, transmembrane area information is not fully considered, the homology of a template is low, and the forecasting accuracy is poor are overcome, and the reliability is high.

Description

technical field [0001] The invention relates to a voltage-gated sodium ion channel structure modeling method based on evolutionary coupling analysis, which belongs to the field of structural biology, and in particular relates to eukaryotic voltage-gated sodium ion channel Na v 1.5 Structural modeling method targeting the closed state of the pore domain. Background technique [0002] Na v Channels are the source of neuronal initiation and propagation of action potentials, changing membrane potential through their rapid opening and closing. Na v The channel has three different functional states, in which the opening and closing of its pore domain (Pore domain) controls the selective passage of ions. At the same time, this domain is also an important binding region for many local anesthetic antiarrhythmic drugs. Many local anesthetic antiarrhythmic drugs are considered Na v Inhibitors of channels whose inhibitory effects are often enhanced by rapid, repeated stimulation or...

Claims

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Application Information

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IPC IPC(8): G06F19/12G06F19/16
CPCG16B5/00G16B15/00
Inventor 纪晓峰盛军郑媛王致鹏
Owner YELLOW SEA FISHERIES RES INST CHINESE ACAD OF FISHERIES SCI
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