CN106496301B - Method for screening food-borne antioxidant oligopeptides by multi-site molecular docking in Keap1Kelch region - Google Patents
Method for screening food-borne antioxidant oligopeptides by multi-site molecular docking in Keap1Kelch region Download PDFInfo
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Abstract
The invention discloses a method for screening food-borne antioxidant oligopeptides by multi-site molecular docking in a Keap1Kelch area, which comprises the following steps: step one, constructing a food-borne oligopeptide molecular structure library; step two, searching for a PDB file which interacts with each other; step three, designing 3 binding sites; step four, carrying out molecular docking on 3 binding sites designed in step three; and step five, comprehensive evaluation, and preliminary screening of food-borne antioxidant oligopeptides. Has the advantages that: by designing multiple binding sites, the impact on alignment assays due to oligopeptides smaller than Nrf2 fragments comprising the ETGE sequence is reduced. In the subsequent test, the food-derived oligopeptides obtained by screening can be used as a blueprint, and the food-derived oligopeptides with the antioxidant function are successively screened out by utilizing an in vitro chemical test and a cell test, so that the test efficiency is effectively improved, and the test period is shortened.
Description
Technical Field
The invention relates to a method for screening food-derived antioxidant oligopeptides, in particular to a method for screening food-derived antioxidant oligopeptides by multi-site molecular docking in a Keap1Kelch region.
Background
Currently, modern medicine generally considers that oxidative stress caused by free radical increase can cause tissue cell damage, further cause organism aging, and even induce malignant tumor in severe cases. Therefore, improving the oxidation resistance of the organism becomes an important means for keeping the health of the body. Compared with other methods for improving the antioxidant capacity of the body, the method for improving the antioxidant capacity of the body is a method with low cost, good effect and high cost performance by eating the food containing the natural antioxidant in daily diet. Among natural antioxidants, food-derived antioxidant peptides occupy an important place.
Food-derived peptides are products of degradation of food proteins and are classified by their size into food-derived oligopeptides (containing 2 to 10 amino acid residues) and food-derived polypeptides (containing more than 10 amino acid residues). Generally, food-derived oligopeptides have greater antioxidant activity as compared to food-derived polypeptides. Antioxidant activity has been studied for a long time as one of the important biological activities of food-derived oligopeptides.
Generally, the method for researching food-derived antioxidant oligopeptides comprises the following 5 steps: (1) carrying out enzymolysis on food-borne protein; (2) separating the enzymolysis crude peptide according to the molecular weight of the peptide; (3) the oxidation resistance is verified by using an in vitro chemical test, a cell test and an animal test; (4) carrying out mass spectrometry analysis test on the crude peptide with antioxidant activity to obtain the molecular structure of the oligopeptide; (5) the antioxidant properties of these oligopeptides were verified by in vitro chemical tests, cell tests and animal experiments. This method is inefficient, costly and time consuming. Meanwhile, the method is not suitable for screening high-activity antioxidant oligopeptides from a large amount of oligopeptides. Therefore, it is urgent to develop a method for screening food-derived antioxidant oligopeptides with high efficiency, economy and rapidness.
Disclosure of Invention
The invention aims to develop a method for efficiently, economically and quickly screening food-derived antioxidant oligopeptides by molecular docking, and provides a method for screening food-derived antioxidant oligopeptides by multi-site molecular docking in a Keap1Kelch region.
The invention provides a method for screening food-borne antioxidant oligopeptides by multi-site molecular docking in a Keap1Kelch area, which comprises the following steps:
step one, obtaining a protein primary structure of a food-borne protein from a Uniprot database, and constructing a food-borne oligopeptide molecular structure library on the basis of the protein primary structure;
step two, searching a PDB file capable of reflecting interaction between a Kelch region of Keap1 protein and an Nrf2 fragment containing an ETGE sequence from a PDB database;
step three, respectively taking three standards of combining a binding site of Keap1 with Nrf2 of the PDB file, all amino acid residues on Keap1 which are in close contact with a Nrf2 fragment and an ETGE sequence at a key position of the Nrf2 fragment as references, and designing 3 binding sites;
step four, taking all oligopeptides in the oligopeptide molecular structure library as ligands, taking Keap1 protein Kelch areas in the PDB file as receptors, and carrying out molecular docking on 3 binding sites designed in step three;
and step five, evaluating the docking result by taking the binding capacity as an index, comparing and analyzing the interaction between the oligopeptide ligand with the front binding capacity and the active center with the interaction between the original Keap1 protein Kelch region and the Nrf2 fragment containing the ETGE sequence in the PDB file, comprehensively evaluating, and preliminarily screening the food-borne antioxidant oligopeptides.
And 3 binding sites are designed, so that the influence on the alignment test caused by the fact that the oligopeptide is smaller than the Nrf2 fragment containing the ETGE sequence in the PDB file is reduced.
The mechanism of the invention is as follows:
the Keap1-Nrf2 signaling pathway is one of the important cellular defense mechanisms of the body in response to oxidative stress. Under normal physiological conditions, Nrf2 is continuously produced in vivo, and Keap1 protein is combined through a BTB region thereof to form a homodimer and is bound to actin of cells, and is respectively combined with DLG and ETGE sequences of a Neh2 region of Nrf2 protein through two Kelch regions of the dimer (wherein the binding capacity between the Kelch regions and the ETGE sequences is 100 times of that of the Kelch regions and the DLG sequences), so that the Nrf2 protein is ubiquitinated and degraded. While the foreign oxidant alters the conformation of the cysteine residues in the BTB and IVR domains of the Keap1 protein when the organism is subjected to oxidative stress, thereby altering the conformation of the Keap1 dimer, which may interfere with the interaction of Keap1 with low affinity DLG sequences, but not with ETGE sequences. And then Nrf2 bound with Keap1 cannot be ubiquitinated and degraded, and finally, the accumulation of Nrf2 in cells is caused. The part of Nrf2 enters the cell nucleus and activates the expression of related genes of a series of II-phase detoxification enzymes (including HO-1, NQO1, SOD and CAT) with antioxidant and cytoprotective effects, thereby improving the antioxidant capacity of the organism.
Therefore, if the external antioxidant active substances can influence the interaction of Keap1-Nrf2, so as to increase the content of Nrf2 in cells, the pathway can be activated, and the antioxidant capacity of the organism can be improved. The antioxidant active which affects the Keap1-Nrf2 interaction in this way is called Keap1-Nrf2 interaction inhibitor. Inhibitors of the Keap1-Nrf2 interaction can be divided into two broad categories: indirect inhibitors and direct inhibitors. The indirect inhibitor is to change the key cysteine residue conformation of BTB and IVR domains of the Keap1 protein, thereby inhibiting Keap1-Nrf2 interaction and further activating a pathway. And the direct inhibitor is directly combined with a Kelch region of the Keap1 protein and occupies the position where the Keap1 is combined with the Nrf2, so that the interaction of the Keap1-Nrf2 is inhibited, and then the pathway is activated. Compared with indirect inhibitors, the direct inhibitors have stronger specificity, and have no side effect of influencing the normal physiological function of other proteins containing key cysteine residues in vivo due to the existence of the indirect inhibitors which have the capability of changing the conformation of the cysteine residues. Direct inhibitors are therefore more suitable for investigation than indirect inhibitors.
In the interaction of the Keap1-Nrf2, the combination of a Keap1 protein Kelch region and an Nrf2 protein ETGE sequence is particularly critical, and if a foreign antioxidant can occupy the combination site of the Keap1 protein Kelch region and the Nrf2 protein ETGE sequence, the foreign antioxidant is most likely to directly inhibit the interaction of the Keap1-Nrf2, so that a Keap1-Nrf2 signal channel is activated, and the antioxidant capacity of the organism is improved.
Based on the mechanism, in the invention, the protein primary structure of the food-borne protein is found from a Uniprot database, and a food-borne oligopeptide molecular structure library is constructed according to the protein primary structure; secondly, selecting a PDB file capable of reflecting interaction between a Kelch region of the Keap1 protein and an Nrf2 fragment containing an ETGE sequence in a PDB database as a receptor file, and designing 3 new binding sites by respectively taking three standards of a binding site of the Nrf2 fragment containing the ETGE sequence and Keap1, all amino acid residues on the Keap1 which is in close contact with the Nrf2 fragment and an ETGE sequence at a key position of the Nrf2 fragment in the receptor file as references; then, utilizing molecular docking software to perform molecular docking of the receptor and oligopeptide molecular structure library at the selected 3 sites respectively, and primarily selecting food-borne oligopeptides with antioxidant effect; and finally, screening again by using an in vitro chemical test to verify the oxidation resistance of the strain.
The invention has the beneficial effects that:
the invention can efficiently and quickly screen dozens of food-derived oligopeptides with stronger antioxidant activity from thousands to tens of thousands of food-derived oligopeptides by molecular docking screening based on Keap1 protein Kelch region. Meanwhile, by designing multiple binding sites, the effect on alignment experiments due to the fact that oligopeptides are smaller than Nrf2 fragments containing ETGE sequences is reduced. In the subsequent test, the food-derived oligopeptides obtained by screening can be used as a blueprint, and the food-derived oligopeptides with the antioxidant function are successively screened out by utilizing an in vitro chemical test and a cell test, so that the test efficiency is effectively improved, and the test period is shortened.
Drawings
FIG. 1 is a schematic representation of the interaction of the Kelch region of the PDB file (PDB ID:2FLU) Keap1 protein with a Nrf2 fragment containing the ETGE sequence of the present invention.
FIG. 2 is a schematic representation of the interaction of Asp-Lys-Lys of the present invention with the Kelch region of the Keap1 protein.
FIG. 3 is a diagram showing the results of the Asp-Lys-Lys fluorescence polarization assay of the present invention.
Detailed Description
Example 1 a multi-site molecular docking screen based on Keap1Kelch region, egg white source antioxidant tripeptide.
The molecular docking screening step comprises the following steps:
1. acquiring a protein primary structure of egg white protein from a Uniprot database, and constructing an egg white source tripeptide molecular structure library on the basis of the protein primary structure;
and (3) obtaining egg white protein by using a Uniprot protein database, obtaining a primary protein structure of the egg white protein, and establishing an egg white source tripeptide molecular structure library based on the primary protein structure.
2. Searching PDB database for PDB file (PDB ID:2FLU) reflecting interaction between Kelch region of Keap1 protein and Nrf2 fragment containing ETGE sequence;
using the PDB database, all PDB files containing human-derived Keap1 were searched, from which PDB files (PDB ID:2FLU) reflecting Keap1-Nrf2 interactions were screened and downloaded.
3. 3 binding sites are designed by respectively taking three criteria of combining a binding site of Keap1 by Nrf2 of the PDB file, all amino acid residues on Keap1 which are in close contact with a Nrf2 fragment and an ETGE sequence at a key position of the Nrf2 fragment as references;
in this step, first, the binding of the Kelch region of the Keap1 protein to the Nrf2 fragment containing the ETGE sequence was analyzed and the original binding site was found in the PDB file (PDB ID:2FLU) in which the Keap1 protein Kelch region was bound to the Nrf2 fragment (containing the ETGE sequence, consisting of 16 amino acid residues) at the site (x: 2.28, y: 6.23, z: 1.63; radius:
) Combining; secondly, since the Nrf2 fragment consists of 16 amino acid residues which are far larger than tripeptide consisting of 3 amino acid residues, in order to reduce the influence on the alignment test caused by the difference, three criteria of the site, all amino acid residues on the Keap1 which are in close contact with the Nrf2 fragment and the key position ETGE sequence of the Nrf2 fragment are respectively used as the basis for designing a new binding site, and the three criteria are adjusted to finally obtain 3 binding sites: binding site 1 (center coordinates: x: -4, y: 6, z: 0; radius:
) Binding site 2 (central coordinates: x: 5, y: 9, z: 1; radius:
) And binding site 3 (central coordinates: x: 7.36, y: 8.33, z: 1.77; radius:
)。
4. taking all tripeptides in the egg white source tripeptide molecular structure library as ligands, taking Keap1 protein Kelch area in PDB file as a receptor, and carrying out molecular docking on 3 binding sites designed in the step 3, wherein the main steps are as follows:
(1) and (3) adding MMFF force field to all tripeptide ligands of the molecular structure library constructed in the step (3), and performing energy minimization until the molecular conformation of the ligands is not changed.
(2) And (3) removing water molecules and Nrf2 fragments from the 2FLU file obtained in the step (1), and carrying out hydrogenation and treatment to obtain a receptor file.
(3) And (3) attaching a CHARMM force field to the receptor file obtained in the step (1).
(4) The three binding sites obtained in step 2 were each set on the receptor file with the CHARMm force field attached.
(5) And (4) taking the receptor obtained in the step (3) as a receptor, and performing molecular docking screening on three selected sites by taking the tripeptide obtained in the step (1) as a ligand.
5. Evaluating the docking result by taking the binding capacity as an index, comprehensively evaluating, and primarily screening the egg white source antioxidant tripeptide.
Sorting the docking results obtained by screening in the step 4, and primarily selecting egg white source tripeptide with antioxidation. In order to further improve the accuracy of the screening result, according to the ordering of the docking result, the interaction of the tripeptide ligand with the active center in the front order and the interaction of the Kelch region of the original Keap1 protein and the Nrf2 fragment containing the ETGE sequence in the PDB file (shown in figure 1) are compared and analyzed, and the egg white source tripeptide with the antioxidation effect is selected.
Through the screening, tripeptides with the top ten orders are screened in three sites respectively. They bind to some of the amino acid residues in the Kelch region of the Keap1 protein and interact with them. These amino acid residues also play a role in the interaction of the Kelch region of the Keap1 protein with Nrf2 fragments containing ETGE sequences. This further demonstrates that binding to the Kelch region of the Keap1 protein modulates this pathway and thereby exerts its antioxidant effect.
And (II) screening the egg white source tripeptide with the anti-oxidation function by using a fluorescence polarization test.
Through the molecular docking screening, a series of tripeptides capable of being combined with three newly set sites of the keap1 in the Kelch region are screened from the egg white source tripeptide ligand library. Then, a fluorescence polarization test is carried out on the mixture, and the oxidation resistance of the mixture is verified.
1. From egg white source tripeptides obtained by molecular docking screening, one compound is randomly selected: Asp-Lys-Lys, the molecular structure of which is shown as the following formula. The interaction with the Kelch region of the Keap1 protein is shown in FIG. 2. This compound was selected for the following fluorescence polarization assay.
The well plate used for fluorescence polarization is a black 384-well plate without binding capacity, and 40 microliters of the solution to be detected is added to each well. The test solution of the test group consisted of 10ul PBS,10ul 4mM Asp-Lys-Lys, 10ul gradient Keap1 protein Kelch region and 10ul 200nM probe. Control solutions were composed of 20ul PBS, a 10ul gradient of Keap1 protein Kelch region and 10ul 200nM probe. After the probe is a FITC-labeled Nrf2 fragment (comprising an ETGE sequence and consisting of 9 amino acid residues) added to a well, the well is covered, and an Fp value is measured after shaking for 30min under the condition of room temperature and light shielding, wherein Kd values of a Keap1 protein Kelch area and an Nrf2 fragment comprising the ETGE sequence are used as evaluation indexes. As shown in FIG. 3, the Kd value of the test group to which Asp-Lys-Lys was added was much higher than that of the control group, indicating that Asp-Lys-Lys inhibits the keap1-Nrf2 interaction. And (4) conclusion: Asp-Lys-Lys has been shown to have the ability to bind keap1 in vitro chemical assays and to be further used in cell assays.
2. The albumen tripeptide obtained after molecular docking screening can be subjected to fluorescence polarization test according to the method of Asp-Lys-Lys, so as to determine whether the albumen tripeptide has the capability of combining with keap1 in an in vitro chemical test, and further determine the oxidation resistance of the albumen tripeptide.
Example 2 a multi-site molecular docking screen for soybean-derived antioxidant tetrapeptides based on the Keap1Kelch region.
The method is the same as example 1, except that: building a molecular structure library; finding out the protein primary structure of the soybean protein from a Uniprot database, and establishing a soybean-derived tetrapeptide molecular structure library based on the protein primary structure.
SEQUENCE LISTING
<110> Jilin university
<120> method for screening food-derived antioxidant oligopeptides by multi-site molecular docking in Keap1Kelch region
<130>2016
<160>1
<170>PatentIn version 3.5
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<211>624
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<213> human (human)
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Asn Arg Thr Phe Ser Tyr Thr Leu Glu Asp His Thr Lys Gln Ala Phe
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Gly Ile Met Asn Glu Leu Arg Leu Ser Gln Gln Leu Cys Asp Val Thr
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Leu Gln Val Lys Tyr Gln Asp Ala Pro Ala Ala Gln Phe Met Ala His
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Asn Gly Leu Arg Glu Gln Gly Met Glu Val Val Ser Ile Glu Gly Ile
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His Pro Lys Val Met Glu Arg Leu Ile Glu Phe Ala Tyr Thr Ala Ser
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Met Tyr Gln Ile Asp Ser Val Val Arg Ala Cys Ser Asp Phe Leu Val
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Gln Gln Leu Asp Pro Ser Asn Ala Ile Gly Ile Ala Asn Phe Ala Glu
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His Cys Gln Leu Val Thr Leu Ile Ser Arg Asp Asp Leu Asn Val Arg
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Cys Glu Ser Glu Val Phe His Ala Cys Ile Asn Trp Val Lys Tyr Asp
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Cys Glu Gln Arg Arg Phe Tyr Val Gln Ala Leu Leu Arg Ala Val Arg
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Glu Ile Leu Gln Ser Asp Ser Arg Cys Lys Asp Tyr Leu Val Lys Ile
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Gln Ser Leu Ser Tyr Leu Glu Ala Tyr Asn Pro Ser Asp Gly Thr Trp
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Claims (1)
1. A method for screening food-derived antioxidant oligopeptides by multi-site molecular docking in a Keap1Kelch area is characterized by comprising the following steps: the method comprises the following steps:
step one, obtaining a protein primary structure of a food-borne protein from a Uniprot database, and constructing a food-borne oligopeptide molecular structure library on the basis of the protein primary structure;
step two, searching a PDB file capable of reflecting interaction between a Kelch region of Keap1 protein and an Nrf2 fragment containing an ETGE sequence from a PDB database, wherein the PDB file is ID:2 FLU;
step three, respectively taking three standards of combining a binding site of Keap1 with Nrf2 of the PDB file, all amino acid residues on Keap1 which are in close contact with a Nrf2 fragment and an ETGE sequence at a key position of the Nrf2 fragment as references, and designing 3 binding sites; center coordinates of binding site 1: x: -4, y: 6, z: 0; radius:
center coordinates of binding site 2: x: 5, y: 9, z: 1; radius:
center coordinates of binding site 3: x: 7.36, y: 8.33, z: 1.77; radius:
step four, taking all oligopeptides in the oligopeptide molecular structure library as ligands, taking Keap1 protein Kelch areas in the PDB file as receptors, and carrying out molecular docking on 3 binding sites designed in step three;
and step five, evaluating the docking result by taking the binding capacity as an index, comparing and analyzing the interaction between the oligopeptide ligand with the front binding capacity and the active center with the interaction between the original Keap1 protein Kelch region and the Nrf2 fragment containing the ETGE sequence in the PDB file, comprehensively evaluating, and preliminarily screening the food-borne antioxidant oligopeptides.
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