CN108733972A - The method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane - Google Patents
The method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane Download PDFInfo
- Publication number
- CN108733972A CN108733972A CN201811094639.5A CN201811094639A CN108733972A CN 108733972 A CN108733972 A CN 108733972A CN 201811094639 A CN201811094639 A CN 201811094639A CN 108733972 A CN108733972 A CN 108733972A
- Authority
- CN
- China
- Prior art keywords
- opfrs
- biomimetic membrane
- film
- prediction
- value
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The method that the present invention provides assessment and prediction organophosphate ester flame retardant damages Biomimetic membrane, belongs to urban eco landscape forest strategy field.Include the following steps：The impedance value that 16 kinds of typical case OPFRs act on Biomimetic membrane is determined by AC impedence method, impedance value size is used to characterize the degree of injury to film.Using successive Regression and Partial Least Squares screening molecular descriptor and QSAR models are constructed, damages of the OPFRs to Biomimetic membrane in application domain is assessed and predicted to the microcosmic effect mechanism for explaining OPFRs and Biomimetic membrane interaction.The QSAR models that the present invention establishes have the good goodness of fit and robustness.The data of the method for the present invention are easily obtained, of low cost, convenient and efficient, save a large amount of human and material resources and experimental period, can accurately analyze the mechanism of action of OPFRs and film, and basic theory data are provided for the marine monitoring of OPFRs and urban eco landscape forest.
Description
Technical field
The invention belongs to the Test Strategies of ecology-oriented risk assessment and marine monitoring field, and in particular to it is a kind of assessment and
The method that prediction organophosphate ester flame retardant damages Biomimetic membrane.
Background technology
With the exploitation of marine resources, marine pollution getting worse.Certain emerging polluters are given birth in ocean and ocean
It is detected successively in object.Since polluter ambient concentration is relatively low, it is not enough to cause apparent biological effect at present.But due to
The persistence and bioaccumulation of pollutant itself so that there are huge environmental risks for compound.Wherein, organophosphorus ester hinders
Fire agent（OPFRs）As typical emerging polluter, in ocean water body and biology（Black carp, perch, shellfish）Have in fat
Apparent detection.Report at present about the monitoring of OPFRs environmental exposures is increasing, and Ecological Environment Risk causes extensive pass
Note.Since OPFRs itself is complicated, mechanism of action is various, describes influences of each OPFRs to marine organisms and needs to consume
A large amount of man power and material, so a kind of ecological risk of convenient accurate method assessment OPFRs of invention is extremely necessary.
As brominated flame-retardant（BFRs）Main alternative materials, OPFRs rely on its excellent fire-retardant and plasticizing property,
Production and usage amount gradually increase, and become emerging environmental pollutants.Due to OPFRs not with host polymer material chemical bond
It closes, to be more easy to, by volatilization, leach or the modes such as abrasion are diffused into surrounding medium, cause a large amount of OPFRs general in the environment
Store-through exists.Studies have shown that OPFRs has toxic effect, tricresyl phosphate to nervous system and immune system（Bis- chloro isopropyls of 1,3-）
Ester（TDCPP）By inhibiting the DNA synthesis of PC12 cells, reduces cell quantity and change Neural Differentiation so as to cause neurodevelopment
Toxicity；TDCPP is by changing Hypothalamus-Pituitary-Thyroid in zebrafish embryo/larva（HPT）The mRNA of axis is expressed and then is changed
Become whole body Concentration of Thyroid Hormones.
Biomembrane resists first extraneous of barrier as organism, and the integrality of membranous system is for the normal life of cell
It is most important for activity.Some researches show that observe the tributyl phosphate of high concentration under 200 times of phase contrast microscopes（TBP）
With three（2- butoxyethyl groups）Phosphate（TBEP）Exposure can cause cellular dysmorphology, destroy membrane structure.In marine organisms fat
The high concentration OPFRs of detection may generate toxic effect to organism.Whether OPFRs is by destroying cell membrane or its other party
Formula and membrane interaction, and then it is a urgent problem to be solved to generate toxic effect.
The structure and function of biomembrane complexity is unfavorable for studying the interaction between film and substance, structure Biomimetic membrane system
System is basis and the premise for studying biomembrane.Biofilm system includes double lipid membrane, Self_assembled monolayers, solid support
Bilayer lipid membrane etc., wherein solid support bilayer lipid membrane have good electrification compared to traditional class ester film
Characteristic and stability are learned, suitable for the interaction between research film and compound.
The structure change of Biomimetic membrane can be characterized using electrochemical techniques.Electrochemical techniques used at present are mainly wrapped
Include cyclic voltammetry（CV）With electrochemical AC impedance method（EIS）.Wherein EIS is the electric signal interfering body by inputting small amplitude
System generates corresponding output signal, and then linear fit obtains frequency response function.A series of one group measured under different frequencies
Frequency response function value forms electrochemical impedance spectroscopy, can be used in the variation for detecting membrane structure.
Application of the QSAR models in terms of the explanation of toxicity of compound mechanism and prediction is increasingly extensive.Model is by studying chemical combination
The analysis of compounds such as the molecular structure information of object such as structured coding, topology parameter, Quantum chemical parameters, physicochemical property parameter
Environmental behaviour and toxicological effect.
Currently, the repercussion study between OPFRs and biomembrane is based on experiment test more, such as pass through fluorescence probe and electricity
Influences of the laboratory facilities research OPFRs such as mirror to film.But it measures a variety of OPFRs with different substituents and needs to consume largely
Man power and material.It is badly in need of inventing a kind of method that simple and efficient assessment OPFRs damages Biomimetic membrane, for assessing
The ecological risk of OPFRs.
Invention content
In view of the above technical problems, the present invention provides a kind of convenience, the assessment of efficient, time saving and energy saving method and prediction
Damages of the OPFRs to Biomimetic membrane provides basic theory data for the marine monitoring of OPFRs and urban eco landscape forest.
The technical solution adopted by the present invention is：The side that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane
Method builds QSAR models according to OPFRs to the impedance value that Biomimetic membrane acts on；According to software computational representation OPFRs's to be measured
The molecular descriptor of molecular structure carries out the assessment and prediction that OPFRs damages Biomimetic membrane by QSAR models.
The OPFRs measures the impedance value that Biomimetic membrane acts on by electrochemical AC impedance method.
The Biomimetic membrane is phospholipid bilayer biomembrane.
The OPFRs is 16 kinds, including the OPFRs of the cyclosubstituted OPFRs of 8 benzene, 2 chlorine substitution, 5 replace containing alkyl
OPFRs and 1 alkoxy substitution OPFRs.
The QSAR models are as follows：
logY = -1.82 × DLS_04 - 4.35 × 10-2 CATS2D_05_PL + 1.22 × 10-1 Mor04 V
- 9.33 × 10-3 RDF080m - 4.80 × 10-1 GATS6m + 3.00 × 10-1 GATS7p
+ 1.70
Wherein, logYFor the logarithm of the OPFRs impedance values acted on Biomimetic membrane,DLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7pFor molecular descriptor；DLS_04Indicate quasi-medicated property index,RDF080mIndicate atom
The radial distribution function of quality weighting,GATS6m、GATS7pRespectively indicate that quality weighting, polarizability weightGearyFrom phase
Close index, CATS2D_05_PLIndicate molecule oleophylic lipophilic characteristics,Mor04 V Indicate weighted based on atom Van der waals volumes three
Tie up molecular structure.
The molecular descriptorDLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7pBy with
Lower step obtains：
The molecular structure of OPFRs is optimized, Molecular structure descriptor is calculated using Dragon softwares, is obtained by successive Regression
To 9 descriptors；
1）First, the partial least square model for including 9 variables is established, corresponding variance of dependent variable ratio is obtainedQ 2 CUM；
2）Then, each descriptor is rejected from partial least square model successively, obtains a series of including the inclined of 8 descriptors
Least square model and correspondingQ 2 CUM, compareQ 2 CUMThe size of value and threshold value,Q 2 CUMValue is bigger, and the performance of model is better；
3）Then in step 2）A series of partial least square models of gained, selectionQ 2 CUMSome model being greater than the set value, after
It is continuous to reject a variable, that is, descriptor, obtain new offset minimum binary equation andQ 2 CUM, return to step 3）, traverse all 8
Partial least square model；
4）For each new offset minimum binary equation, different variables is rejected successively, obtains a series of offset minimum binary equations
WithQ 2 CUMValue, more each offset minimum binary equation are correspondingQ 2 CUMValue selects maximumQ 2 CUMCorrespondingDLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7p 6 descriptors build QSAR models, are acted on for explanation
Mechanism.
The molecular descriptor of the molecular structure according to software computational representation OPFRs to be measured is carried out by QSAR models
The assessment and prediction that OPFRs damages Biomimetic membrane include the following steps：
The molecular structure of OPFRs to be measured is optimized, the molecular descriptor of OPFRs to be measured is obtained using Dragon softwares：DLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7p；
Molecular descriptor is substituted into QSAR models, obtains the logarithm log for the impedance value that OPFRs to be measured acts on Biomimetic membraneY；
According to logYDamages of the OPFRs to Biomimetic membrane is assessed and predicted with molecular descriptor.
It is described according to logYAssess and predict that OPFRs is specially to the damage of Biomimetic membrane with molecular descriptor：
The size of impedance value represents the potassium ferricyanide molecular probe in electrolyte and reaches the drag size being subject to when gold electrode surfaces；
logYIt is worth smaller, the resistance that is subject to is smaller when molecular probe reaches gold electrode surfaces, the easier intrusion cell film inner layer of compound,
The integrality of disrupting biofilm so that other compounds are more easy to cause body injury into film；logYValue is bigger, and molecular probe arrives
The resistance being subject to when up to gold electrode surfaces is bigger, it is easier to stronger dipole-induced dipole occur with the large biological molecule on film
Effect generates interaction with receptor protein, interferes signal transmission and related pathways on film.
It is described to assess and predict that OPFRs is specific as follows to the damage of Biomimetic membrane according to logarithm and molecular descriptor：
First,DLS_04WithGATS7pIt is the key factor for influencing OPFRs and membrane interaction：
DLS_04Value is bigger, replaces the space structure of functional group and steric hindrance smaller contained in molecule, the film modified electricity of measurement
Pole impedance value is smaller, and compound is easier to interact with biosystem, invade cell film inner layer, disrupting biofilm it is complete
Whole property so that other compounds are more easy to cause body injury into film；
GATS7pValue is bigger, and atom polarization ability is stronger, and the ability for obtaining dipole is also stronger, the film modified electrode resistance of measurement
Anti- value is bigger, it is easier to stronger dipole-induced dipole occur with the large biological molecule on film and act on, to assemble on film；
The electronegativity of functional group containing halogen substitution and alkoxy substitution in molecule is stronger, easier to generate phase interaction with receptor protein
With the signal on interference film transmits and related pathways；
Secondly,CATS2D_05_PL, three-dimensional arrangement and the space structure of atom also influence the interaction of OPFRs and biomembrane.
The OPFRs to be measured includes in alkyl phosphate, alkoxy phosphate, halogenated alkyl phosphate and aryl phosphate ester
One kind.
Beneficial effects of the present invention and advantage are as follows：
The present invention is carried by building micromechanisms of the QSAR scale-model investigations OPFRs to membrane damage for the urban eco landscape forest of OPFRs
For basic data.The QSAR models that the present invention is built accurately can easily evaluate in application domain OPFRs to Biomimetic membrane
Damage, the application domain of model includes 4 classes such as alkyl phosphate, alkoxy phosphate, halogenated alkyl phosphate and aryl phosphate ester
16 kinds of OPFRs of different substituents.The QSAR models of foundation are simple and efficient, easy to operate, application domain is wide, can save experiment and survey
Required a large amount of manpower and materials are tried, basic data is provided for the risk assessment and marine monitoring of OPFRs.
The method of the present invention only needs the descriptor of computational representation compound structure, can be simple and direct accurate by QSAR models
Ground judges its damage to Biomimetic membrane.
Description of the drawings
Fig. 1 is the flow chart of the present invention；
Fig. 2 is the equivalent circuit diagram for being fitted AC impedance modal data；
Fig. 3 is logYMeasured value and predicted value fitted figure；
Fig. 4 is the Euclidean distance figure for characterizing application domain；
Fig. 5 is the Williams figures for characterizing application domain.
Specific implementation mode
The present invention is described in further detail in conjunction with the accompanying drawings and embodiments.
The present invention determines the impedance of the film modified electrode under 16 kinds of typical case's OPFRs effects by electrochemical AC impedance method
Value.Using successive Regression and Partial Least Squares（PLS）QSAR models are established, microcosmic works of the OPFRs to membrane damage is illustrated
With mechanism, damages of the OPFRs to Biomimetic membrane in assessment and prediction application domain, marine monitoring and the ecological risk for being OPFRs
Assessment provides basic theory data.
It builds QSAR model evaluations and predicts damages of the OPFRs to film.
The Biomimetic membrane model is the phospholipid bilayer life built in gold electrode surfaces by " frost-smearing " method
Object film.First, gold electrode passes through " Au-S " to 2- dipalmitoyl-glycerols -3- phosphoric acid mercaptoethanol (DPPTE) molecule with treated
Covalent bond forms monofilm；Phospholipid bilayer is then gone out in single layer film surface addition DPPC layer buildings using " smear-freeze " method
Tunic.Film modified electrode impedance value under different OPFRs effects is measured using electrochemical AC impedance method.
Structure optimization is carried out to 16 kinds of OPFRs of research, the structure after optimization is imported into Dragon softwares, table is calculated
4885 descriptors for levying molecular structure choose descriptor by method of gradual regression, QSAR moulds are established using Partial Least Squares
Type.
The QSAR models are：
logY = -1.82 × DLS_04 - 4.35 × 10-2 CATS2D_05_PL + 1.22 × 10-1 Mor04 V
- 9.33 × 10-3 RDF080m - 4.80 × 10-1 GATS6m + 3.00 × 10-1 GATS7p
+ 1.70
n =16,R 2 adj=0.881,F=119.45,SE=0.114,p<0.001 (95% confidence interval),
R 2 X=0.735,R 2 Y=0.905,Q 2 CUM=0.778,RMSE = 0.110
In QSAR models, the quasi-medicated property index of compound（DLS_04）And polarizability（GATS7p）It is to influence OPFRs and film
The key factor of interaction.DLS_04Value is bigger, replaces the space structure of functional group and steric hindrance smaller contained in molecule, surveys
Fixed film modified electrode impedance value（logY）Bigger, compound is easier to interact with biosystem, invades cell
Film inner layer, the integrality of disrupting biofilm so that other compounds are more easy to cause body injury into film.GATS7pValue is bigger,
Atom polarization ability is stronger, and the ability for obtaining dipole is also stronger, the film modified electrode impedance value of measurement（logY）It is smaller, more
It is easy that stronger dipole-induced dipole effect occurs with the large biological molecule on film, on film assemble.Contain halogen in molecule
The electronegativity of the functional group of element substitution and alkoxy substitution is stronger, easier to generate interaction with receptor protein, interferes on film
Signal transmit and related pathways.Secondly, the three-dimensional arrangement of the oleophylic lipophilicity of compound, atom can also be influenced with space structure
The interaction of OPFRs and film.
The invention is established by calculating 16 kinds of OPFRs molecular structure of compounds parameters about structural parameters and impedance value
QSAR models, the mechanism of action damaged to film modified electrode for analyzing OPFRs carry for OPFRs ecological risk assessments and management
Data for reference.As shown in Figure 1, including the following steps：
（1）The structure of gold electrode surfaces supported bilayer lipid membrane
3000 mesh sand paper of gold electrode are polished, chamois leather is then used（Alumina powder and water）Gold electrode is polished, after polishing
It is cleaned in gold electrode absolute ethyl alcohol and ultra-pure water, the electrode after cleaning is placed in the mixed solution (concentrated sulfuric acid-peroxidating now matched
Hydrogen volume ratio is 3：1) 3 min are impregnated in, to remove electrode surface impurity.Electrode ultrapure water is taken out, after flushing
Electrode is connected to electrochemical workstation, using the sulfuric acid solution of 0.1 mol/L as electrolyte, by cyclic voltammetry (CV) into
Row electric potential scanning, further to remove the impurity of electrode surface.0 ~ 1.6 V of potential region, 100 mV/s of sweep speed, scanning
It 20 weeks, is cleaned using ultra-pure water after the completion of scanning, drying is spare.
DPPTE powder is dissolved in absolute ethyl alcohol, 2 mmol/L DPPTE solution are configured to.DPPC powder is dissolved in
In n-decane, the DPPC n-decane solutions of a concentration of 20 mg/mL are made.It is anhydrous that 0.5 mL DPPTE are added into 1.5 mL EP
Above-mentioned spare gold electrode is immersed 16 h of DPPTE solution by ethanol solution, and DPPTE molecules are covalent by the sulfydryl and gold on head
In conjunction with formation " Au-S " key, monofilm is formed in naked gold electrode surface self-organization.After electrode takes out, with washes of absolute alcohol 2
Min is cleaned with ultra-pure water later with removing the DPPTE molecules of electrode surface Non-covalent binding, after drying, is added dropwise to its surface
The prepared DPPC solution of 10 μ L, after being first placed in about 10 min at room temperature, then 20oC refrigerators place about 30 min, make just
Decane solvent volatilizees.Electrode is taken out after solvent volatilization, places about 15 min at room temperature, it, will be golden after solvent completely volatilization
Electrode, which is placed in 0.1 mol/L KCl solution, impregnates 2 h, DPPC molecules under the collective effect of hydrophilic and hydrophobic forces
DPPTE single layer film surfaces spontaneously form second layer immobilized artificial membrane, as the Biomimetic membrane used in experimental study.
（2）Electrochemistry experiment
Electrochemical AC impedance method can precisely characterize Lipid bilayer membranes as a kind of electrochemical measuring technique, can detection membrane knot
Structure changes.This experiment uses CHI 760D electrochemical workstations, and electrochemistry inspection is carried out to Biomimetic membrane by three-electrode system
It surveys.Electrolyte is 0.1 mol/L potassium chloride, 0.1 mol/L PBS and the 5 mmol/L potassium ferricyanides or potassium ferrocyanide（pH =
6.8）.Using the double-deck film modified gold electrode as working electrode, saturated calomel electrode is reference electrode, and platinum electrode is auxiliary electrode.
Range of scanned frequencies is the kHz of 0.01 Hz ~ 100, and signal amplitude is 5 mV, measures impedance data, uses electrochemistry work
Make station and carry Software on Drawing electrochemical impedance spectrogram, as shown in Fig. 2, the experimental result of EIS is passed through 3.1 Software on Drawing of Zview
Simulating equivalent circuit figure carries out data fitting.RS indicates bath resistance,RM indicates phospholipid bilayer film resistance,QM indicates Chang Xiangwei
Element.
（3）The structure of data set
16 kinds of typical case OPFRs are drawn by ChemDraw Ultra（Table 1）Two-dimensional molecular structure, later use Chem3D
The minimizing energy method of Ultra softwares（Minimum RMS gradients are 0.001）The molecular structure of model compound is tentatively optimized,
Obtain minimum energy configuration.Destination file is inputted into Dragon softwares（https://chm.kode-solutions.net/
products_dragon.php）, computational representation compound atomic type, topology and geometric parameter, three-dimensional arrangement and structure, class
The features such as pharmacological property index 29 class, 4885 molecular descriptors.Table 1 is 16 kinds of typical case's OPFRs essential informations and structure distribution table.
Table 1
（4）The structure of QSAR models
With the impedance value log of 16 kinds of typical lower double-deck film modified gold electrodes of OPFRs effectsYAs QSAR models because becoming
Amount.4885 initial molecular descriptors are subjected to primary dcreening operation by stepwise regression analysis, 9 descriptors is obtained, is respectivelyDLS_ 04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7p、SPH、MATS8V、RDF065e。Using Simca softwares
Middle offset minimum binary (PLS) returns and establishes model.Determine that PLS ingredients are built first using Leave-group-out cross validations
Corresponding variance of dependent variable ratio is calculated in the vertical PLS models for including 9 variables, softwareQ 2 CUM, then by each descriptor
It is rejected from model successively and obtains a series of including the new models of 8 descriptors and corresponding successivelyQ 2 CUM, then repeat
State operating process, every time reject a variable, obtain corresponding offset minimum binary equation andQ 2 CUM, more each model is correspondingQ 2 CUMValue selects maximumQ 2 CUMCorrespondingDLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7p
6 descriptors build QSAR models, the QSAR models for explaining mechanism of action.Q 2 CUMValue is bigger, and the performance of model is better, and one
As thinkQ 2 CUM>=0.5, model has good conspicuousness and predictive ability；Screening obtains according with basic letter described in QSAR models
Breath such as table 2.
Table 2
a DLS_04The quasi-medicated property structure index of old et al. modification
b CATS2D_05_PL Compound oleophylic lipophilicity is described
c Mor04 V Indicate the three-dimensional molecular structure that signal 04 is weighted based on atom Van der waals volumes
d RDF080mIndicate the radial distribution function weighted by atomic mass
e GATS6m is indicatedBy atomic mass weightingGearyAuto-correlation
f GATS7pWhat expression was weighted by atomic polarizabilityGearyAuto-correlation
The expression formula of QSAR models is：
logY = -1.82 × DLS_04 - 4.35 × 10-2 CATS2D_05_PL + 1.22 × 10-1 Mor04 V
- 9.33 × 10-3 RDF080m - 4.80 × 10-1 GATS6m + 3.00 × 10-1 GATS7p
+ 1.70
n =16,R 2 adj=0.881,R 2 X=0.735,R 2 Y=0.905,Q 2 CUM=0.719,RMSE = 0.110
In a model, logYIt is expressed as the function of 6 descriptor variables, training set datan= 16.The statistic of model testingF
=119.45, standard errorSE=0.114, significancep<0.001 (95% confidence interval), the multiple coefficient of determinationR 2 adj =
0.881, multiple correlation coefficient squareR 2 X=0.735, multiple correlation coefficient squareR 2 Y=0.905, mean square deviation errorRMSE =
0.110 shows that model has the good goodness of fit, cross validation coefficientQ 2 CUM=0.719 shows that model has good robustness,
ModelR 2 YWithQ 2 CUMDifference show that model does not have over-fitting less than 0.3.The expression of table 3, the log of 16 kinds of typical OPFRsYReality
Measured value and predicted value, Fig. 3 expressions, the log of 16 kinds of typical OPFRsYMeasured value and predicted value fitting result.Using training
The robustness of collection/verification collection Split Method testing model, cross-validation coefficientQ 2 IN =0.778, illustrate that model has well
Robustness.Diagnostic factro variance inflation factor between each variableVIF <10, tolerancetolerance >0.1, state indicesCondition Index <30, illustrate that serious multicollinearity is independently not present between each independent variable.Table 3 is 16 kinds of allusion quotations
The log of the OPFRs of typeYMeasured value and predicted value.
Table 3
In QSAR models, logYFor the double-deck film modified gold electrode value of relative impedance, DLS_04Compounds pharmacological property index is described,
This index considers a series of property, including when molecule forms hydrogen bond, the quantity of hydrogen bond donor and receptor, lipophilicity and
Index of unsaturation etc.；CATS2D_05_PLCompound oleophylic lipophilic property is described；Mor04 V Description is dissipated by using different angles
Function is penetrated to calculate the summation of all atom Van der waals volumes, indicates shadow of the three-dimensional arrangement to molecular size and shape of atom
It rings；RDF080mThe radial distribution function weighted by atomic mass is described, for indicating specific in specific three-D space structure
Information；GATS6mThe 2D auto-correlation functions that are weighted by quality are described, for indicating specific molecular structure, autocorrelation more it is strong thenGATS6mIt is worth smaller；GATS7pThe atom polarization ability of identical topology distance is described.
Such as table 4, according to descriptor project importance index (VIP) value analysis shows, the quasi-medicated property index of compound（DLS_ 04）And polarizability（GATS7p）It is the key factor for influencing OPFRs and film effect.DLS_04Value is bigger, contained in molecule
Replace space structure and the steric hindrance of functional group smaller, compound is easier to interact with biosystem, invades cell membrane
Internal layer, the integrality of disrupting biofilm so that other compounds are more easy to cause body injury into film.GATS7pValue is bigger, former
Muon polarization ability is stronger, and the ability for obtaining dipole is also stronger, it is easier to stronger dipole-occur with the large biological molecule on film
Induced dipole acts on, to assemble on film.The electronegativity of functional group containing halogen substitution and alkoxy substitution in molecule is got over
By force, easier to generate interaction with receptor protein, interfere signal transmission and related pathways on film.In addition, the oleophylic of chemical combination
Lipophilicity, three-dimensional arrangement and the space structure of atom can also influence the interaction of OPFRs and film.Table 4 is to be retouched in QSAR models
State symbol projection importance index (VIP) value.
Table 4
（5）QSAR model application domains characterize
The application domain of QSAR models is characterized by Euclidean distance figure and Williams figures, such as Fig. 4, Euclidean distance
Figure is less than 1.29 by Ambit discovery v0.04 Software on Drawing, Euclidean distance, and the compound of training set is all in mould
In type application domain, illustrate that the training set of model has good representativeness.Such as Fig. 5, the residual of Williams figure compounds
All exist（- 2.5,2.5）Within, the lever value of compound is respectively less than warning value 1.31, illustrates that model does not have outlier.Pass through characterization
Application domain does not find outlier and misvalues a little, it is ensured that modal analysis results are credible.
In OPFRs data sets constructed by the present invention, including the OPFRs of the cyclosubstituted OPFRs of 8 benzene, 2 chlorine substitution, 5
The OPFRs of a substitution containing alkyl-substituted OPFRs and 1 alkoxy.
Embodiment 1
Tricresyl phosphate（2- ethylhexyls）Ester（TEHP）：Its lever value is calculated using Williams figure methodshiIt is 0.521<h*
(early warning value)=1.31, residual (SE) = 1.40 <2.50, illustrate this compound in QSAR model application domains.It is real
The fixed TEHP impedance values of test are 0.673 compared to being all alkyl-substituted tributyl phosphate（TBP）- impedance value 0.626
It obviously increases, Analysis on Mechanism is carried out according to QSAR models, TEHP is due to the larger branched alkyl substituent of space structure so that characterization is former
Subspace is arranged and the descriptor of three-dimensional structureMor04 V Numerical value increase to 1.95 from 0.147, quasi-medicated property index subtracts from 0.80
It is small to 0.30, characterize atomic polarizabilityGATS7pIncrease to 1.10 from 0.557, so that compound is easier to insertion or attached
Increases the electrode impedance value of film in film outer surface, interferes signal transmission and related pathways on film.
Embodiment 2
Tricresyl phosphate（2- chloroethyls）Ester（TCEP）：Its lever value is calculated using Williams figure methodshiIt is 0.218<h*
(early warning value)=1.31, residual (SE) = -0.484 >- 2.50, illustrate this compound in QSAR model application domains.
The alkyl substitution of the carbochain end of TBP becomes halogen（Cl）Substitution, the halogen of measuring（Cl）Substituted TCEP impedance values are
For 0.0173 compared to alkyl-substituted tributyl phosphate（TBP）Impedance value 0.626 obviously increase, according to QSAR models carry out
Analysis on Mechanism, TCEP replace functional group due to containing halogen, cause compound electronegativity to enhance so that quasi-medicated property index subtracts from 3
It is small to 0, characterize atomic polarizabilityGATS7pIncrease to 0.674 from 0.557, be easy to receptor protein molecule act power insert
Enter or be attached to film outer surface, to increase film modified electrode impedance value, interferes signal transmission and the related pathways on film.
Embodiment 3
Tricresyl phosphate（TMTP）：Its lever value is calculated using Williams figure methodshiIt is 0.678<h* (early warning
Value)=1.31, residual (SE) = -0.911 >- 2.50, illustrate this compound in QSAR model application domains.Experiment
The TMTP impedance values of measurement are for -0.406 compared to being all the cyclosubstituted three p-toluenesuifonic acids ester of virtue（TPTP）Impedance value
0.577 obviously increases, and Analysis on Mechanism, aromatic ring substitution and TMTP is carried out according to QSAR models, due to the substitution of the methyl on phenyl ring
Position is by contraposition to meta position so that the steric hindrance of compound is reduced, the descriptor of characterization atomic space arrangement and three-dimensional structureMor04 V Numerical value be reduced to -0.257 from 0.797, characterize atomic polarizabilityGATS7pIt is reduced to 0.431 from 1.87, characterization
It is fat-solubleCATS2D_05_PLIncrease to 6 from 3, the electrode impedance value of film is made to reduce, compound is more easy to the internal layer of intrusion film, changes
Membrane structure destroys the integrality of film.
Claims (10)
1. the method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane, it is characterised in that：
QSAR models are built to the impedance value that Biomimetic membrane acts on according to organophosphate ester flame retardant, that is, OPFRs；
According to the molecular descriptor of the molecular structure of software computational representation OPFRs to be measured, OPFRs is carried out to mould by QSAR models
The assessment and prediction of quasi- biomembrane damage.
2. the method that assessment according to claim 1 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, the OPFRs measures the impedance value that Biomimetic membrane acts on by electrochemical AC impedance method.
3. the method that assessment according to claim 1 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, the Biomimetic membrane is phospholipid bilayer biomembrane.
4. the method that assessment according to claim 1 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
Be characterized in that, the OPFRs is 16 kinds, including the OPFRs of the cyclosubstituted OPFRs of 8 benzene, 2 chlorine substitution, 5 taken containing alkyl
The OPFRs of OPFRs and 1 alkoxy substitution in generation.
5. the method that assessment according to claim 1 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, the QSAR models are as follows：
logY = -1.82 × DLS_04 - 4.35 × 10-2 CATS2D_05_PL + 1.22 × 10-1 Mor04 V
- 9.33 × 10-3 RDF080m - 4.80 × 10-1 GATS6m + 3.00 × 10-1 GATS7p
+ 1.70
Wherein, logYFor the logarithm of the OPFRs impedance values acted on Biomimetic membrane,DLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7pFor molecular descriptor；DLS_04Indicate quasi-medicated property index,RDF080mIndicate that atomic mass adds
The radial distribution function of power,GATS6m、GATS7pRespectively indicate that quality weighting, polarizability weightGearyAutocorrelation exponent, CATS2D_05_PLIndicate molecule oleophylic lipophilic characteristics,Mor04 V Indicate the three-dimensional molecular knot weighted based on atom Van der waals volumes
Structure.
6. the method that assessment according to claim 5 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, the molecular descriptorDLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7pBy with
Lower step obtains：
The molecular structure of OPFRs is optimized, Molecular structure descriptor is calculated using Dragon softwares, is obtained by successive Regression
To 9 descriptors；
1）First, the partial least square model for including 9 variables is established, corresponding variance of dependent variable ratio is obtainedQ 2 CUM；
2）Then, each descriptor is rejected from partial least square model successively, obtains a series of including the inclined of 8 descriptors
Least square model and correspondingQ 2 CUM, compareQ 2 CUMThe size of value and threshold value,Q 2 CUMValue is bigger, and the performance of model is better；
3）Then in step 2）A series of partial least square models of gained, selectionQ 2 CUMSome model being greater than the set value continues
Reject a variable, that is, descriptor, obtain new offset minimum binary equation andQ 2 CUM, return to step 3）, it is inclined to traverse all 8
Least square model；
4）For each new offset minimum binary equation, different variables is rejected successively, obtains a series of offset minimum binary equations
WithQ 2 CUMValue, more each offset minimum binary equation are correspondingQ 2 CUMValue selects maximumQ 2 CUMCorrespondingDLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7p Totally 6 descriptors build QSAR models, make for explaining
Use mechanism.
7. the method that assessment according to claim 1 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, the molecular descriptor of the molecular structure according to software computational representation OPFRs to be measured is carried out by QSAR models
The assessment and prediction that OPFRs damages Biomimetic membrane include the following steps：
The molecular structure of OPFRs to be measured is optimized, the molecular descriptor of OPFRs to be measured is obtained using Dragon softwares：DLS_04、CATS2D_05_PL、Mor04 V 、RDF080m、GATS6m、GATS7p；
Molecular descriptor is substituted into QSAR models, obtains the logarithm log for the impedance value that OPFRs to be measured acts on Biomimetic membraneY；
According to logYDamages of the OPFRs to Biomimetic membrane is assessed and predicted with molecular descriptor.
8. the method that assessment according to claim 7 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, it is described according to logYAssess and predict that OPFRs is specially to the damage of Biomimetic membrane with molecular descriptor：
The size of impedance value represents the potassium ferricyanide molecular probe in electrolyte and reaches the drag size being subject to when gold electrode surfaces；
logYIt is worth smaller, the resistance that is subject to is smaller when molecular probe reaches gold electrode surfaces, the easier intrusion cell film inner layer of compound,
The integrality of disrupting biofilm so that other compounds are more easy to cause body injury into film；logYValue is bigger, and molecular probe arrives
The resistance being subject to when up to gold electrode surfaces is bigger, it is easier to stronger dipole-induced dipole occur with the large biological molecule on film
Effect generates interaction with receptor protein, interferes signal transmission and related pathways on film.
9. the method that assessment according to claim 7 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, it is described to assess and predict that OPFRs is specific as follows to the damage of Biomimetic membrane according to logarithm and molecular descriptor：
First,DLS_04WithGATS7pIt is the key factor for influencing OPFRs and membrane interaction：
DLS_04Value is bigger, replaces the space structure of functional group and steric hindrance smaller contained in molecule, the film modified electricity of measurement
Pole impedance value is smaller, and compound is easier to interact with biosystem, invade cell film inner layer, disrupting biofilm it is complete
Whole property so that other compounds are more easy to cause body injury into film；
GATS7pValue is bigger, and atom polarization ability is stronger, and the ability for obtaining dipole is also stronger, the film modified electrode resistance of measurement
Anti- value is bigger, it is easier to stronger dipole-induced dipole occur with the large biological molecule on film and act on, to assemble on film；
The electronegativity of functional group containing halogen substitution and alkoxy substitution in molecule is stronger, easier to generate phase interaction with receptor protein
With the signal on interference film transmits and related pathways；
Secondly,CATS2D_05_PL, three-dimensional arrangement and the space structure of atom also influence the interaction of OPFRs and biomembrane.
10. the method that assessment according to claim 7 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, the OPFRs to be measured includes alkyl phosphate, alkoxy phosphate, halogenated alkyl phosphate and aryl phosphate ester
In one kind.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811094639.5A CN108733972B (en) | 2018-09-19 | 2018-09-19 | The method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811094639.5A CN108733972B (en) | 2018-09-19 | 2018-09-19 | The method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108733972A true CN108733972A (en) | 2018-11-02 |
| CN108733972B CN108733972B (en) | 2018-12-21 |
Family
ID=63941904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811094639.5A Active CN108733972B (en) | 2018-09-19 | 2018-09-19 | The method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108733972B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100048077A1 (en) * | 2008-08-20 | 2010-02-25 | Lg Chem, Ltd. | Composition of acrylic pressure-sensitive adhesive and surface finishing material comprising the same |
| CN103971030A (en) * | 2014-04-18 | 2014-08-06 | 中国科学院烟台海岸带研究所 | Method for predicting affinity of interaction between biomarker p53 and organic phosphate fire retardant |
| CN104834831A (en) * | 2015-04-08 | 2015-08-12 | 北京工业大学 | Consistency model building method based on 3-dimensional quantitative structure-activity relationship model |
| CN107300596A (en) * | 2017-07-29 | 2017-10-27 | 浙江大学台州研究院 | A kind of method of the organophosphate ester flame retardant content detection suitable for a variety of foods |
| CN108519415A (en) * | 2018-04-04 | 2018-09-11 | 中国科学院烟台海岸带研究所 | It is a kind of assessment organophosphate ester flame retardant toxicity model and its application |
-
2018
- 2018-09-19 CN CN201811094639.5A patent/CN108733972B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100048077A1 (en) * | 2008-08-20 | 2010-02-25 | Lg Chem, Ltd. | Composition of acrylic pressure-sensitive adhesive and surface finishing material comprising the same |
| CN103971030A (en) * | 2014-04-18 | 2014-08-06 | 中国科学院烟台海岸带研究所 | Method for predicting affinity of interaction between biomarker p53 and organic phosphate fire retardant |
| CN104834831A (en) * | 2015-04-08 | 2015-08-12 | 北京工业大学 | Consistency model building method based on 3-dimensional quantitative structure-activity relationship model |
| CN107300596A (en) * | 2017-07-29 | 2017-10-27 | 浙江大学台州研究院 | A kind of method of the organophosphate ester flame retardant content detection suitable for a variety of foods |
| CN108519415A (en) * | 2018-04-04 | 2018-09-11 | 中国科学院烟台海岸带研究所 | It is a kind of assessment organophosphate ester flame retardant toxicity model and its application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108733972B (en) | 2018-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Vivier et al. | Impedance analysis of electrochemical systems | |
| Qin et al. | Plasticizer-free polymer containing a covalently immobilized Ca2+-selective ionophore for potentiometric and optical sensors | |
| Belmont-Hébert et al. | Gel-integrated microelectrode arrays for direct voltammetric measurements of heavy metals in natural waters and other complex media | |
| Ino et al. | Closed bipolar electrode array for on-chip analysis of cellular respiration by cell aggregates | |
| Lewandowski et al. | Two-dimensional small-scale variability of pore water phosphate in freshwater lakes: results from a novel dialysis sampler | |
| Li et al. | Phosphate sensor using molybdenum | |
| Crespo et al. | Direct detection of acidity, alkalinity, and pH with membrane electrodes | |
| Verrelli et al. | Development of silicon-based potentiometric sensors: towards a miniaturized electronic tongue | |
| Storer et al. | Towards phosphate detection in hydroponics using molecularly imprinted polymer sensors | |
| Mann et al. | Diagnostic criteria for the characterization of quasireversible electron transfer reactions by cyclic square wave voltammetry | |
| Chen et al. | Predicting voltammetry using physics-informed neural networks | |
| WO2013081496A1 (en) | Apparatus and method for determining the toxicity of liquid media | |
| Xu et al. | Equivalent circuit models for a biomembrane impedance sensor and analysis of electrochemical impedance spectra based on support vector regression | |
| Zouaoui et al. | Experimental study and mathematical modeling of a glyphosate impedimetric microsensor based on molecularly imprinted chitosan film | |
| Islam et al. | Voltammetric selectivity in detection of ionized perfluoroalkyl substances at micro-interfaces between immiscible electrolyte solutions | |
| Monari et al. | Factors affecting the electron transfer properties of an immobilized cupredoxin | |
| CN108733972B (en) | The method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane | |
| Jaworska et al. | Implementation of a Chloride‐selective Electrode Into a Closed Bipolar Electrode System with Fluorimetric Readout | |
| Zhai et al. | In vivo monitoring of calcium ions in rat cerebrospinal fluid using an all-solid-state acupuncture needle based potentiometric microelectrode | |
| Town et al. | Chemodynamics of soft nanoparticulate metal complexes: from the local particle/medium interface to a macroscopic sensor surface | |
| Altahan et al. | The use of bi-potentiostat as a simple and accurate electrochemical approach for the determination of orthophosphate in seawater | |
| Markfort et al. | Dissolved oxygen measurements in aquatic environments: the effects of changing temperature and pressure on three sensor technologies | |
| Cheong et al. | Physically tailoring ion fluxes by introducing foamlike structures into polymeric membranes of solid contact ion-selective electrodes | |
| Okabe et al. | A polyphasic approach to study ecophysiology of complex multispecies nitrifying biofilms | |
| WO2023136846A1 (en) | Soil parameter sensor system |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |