CN108733972B - 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
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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.The following steps are included: determining the impedance value that 16 kinds of typical case OPFRs act on Biomimetic membrane 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 model is constructed, for explaining the microcosmic effect mechanism of OPFRs and Biomimetic membrane interaction, damage of the OPFRs to Biomimetic membrane in assessment and prediction application domain.The QSAR model that the present invention establishes has the good goodness of fit and robustness.The data of the method for the present invention are easily obtained, low in 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, provide basic theory data 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 technique
With the exploitation of marine resources, marine pollution is got worse.Certain emerging polluters are raw in ocean and ocean
It is detected successively in object.Since polluter ambient concentration is lower, 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
Agent (OPFRs) is fired as typical emerging polluter, is had in ocean water body and biology (black carp, perch, shellfish) fat
Obvious detection.Report at present about the monitoring of OPFRs environmental exposure is increasing, and Ecological Environment Risk causes extensive pass
Note.Since structure is complicated by OPFRs itself, mechanism of action multiplicity describes influence of each OPFRs to marine organisms and needs to consume
A large amount of man power and material, so the ecological risk for inventing a kind of convenient accurate method assessment OPFRs is extremely necessary.
As the main alternative materials of brominated flame-retardant (BFRs), OPFRs relies 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 easier to leach by volatilization 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 (1,3- bis- chloro isopropyl) to nervous system and immune system
Ester (TDCPP) reduces cell quantity and simultaneously changes Neural Differentiation so as to cause neurodevelopment by inhibiting the DNA of PC12 cell to synthesize
Toxicity；TDCPP is changed by changing the mRNA expression of Hypothalamus-Pituitary-Thyroid (HPT) axis in zebrafish embryo/larva
Become whole body Concentration of Thyroid Hormones.
Biomembrane resists extraneous first barrier, the integrality of membranous system life normal for cell as organism
It is most important for activity.Some researches show that observe the tributyl phosphate (TBP) of high concentration under 200 times of phase contrast microscopes
It will cause cellular dysmorphology with the exposure of three (2- butoxyethyl group) phosphates (TBEP), destroy membrane structure.In marine organisms fat
The high concentration OPFRs of detection may generate toxic effect to organism.Whether OPFRs, which passes through, is destroyed cell membrane or its other party
Formula and membrane interaction, and then generating toxic effect is a urgent problem to be solved.
The structure and function of biomembrane complexity is unfavorable for studying the interaction between film and substance, constructs 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 has 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) and 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.
QSAR model toxicity of compound mechanism explain and prediction in terms of using increasingly extensive.Model passes through research 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
Influence of the laboratory facilities research OPFRs such as mirror to film.But a variety of OPFRs with different substituents of measurement need 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.
Summary of the invention
In view of the above technical problems, the present invention provides a kind of convenience, efficient, time saving and energy saving method assessment and prediction
Damage 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 that: assess and predict the side that organophosphate ester flame retardant damages Biomimetic membrane
Method constructs QSAR model to the impedance value that Biomimetic membrane acts on according to OPFRs；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 model.
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, the OPFRs that replaces including the cyclosubstituted OPFRs of 8 benzene, 2 chlorine, 5 replace containing alkyl
OPFRs and 1 alkoxy replace OPFRs.
The QSAR model is as follows:
LogY=-1.82 × DLS_04-4.35 × 10-2CATS2D_05_PL+1.22×10-1Mor04V-9.33×10- 3RDF080m-4.80×10-1GATS6m+3.00×10-1GATS7p+1.70
Wherein, logY is the logarithm of impedance value that OPFRs acts on Biomimetic membrane, DLS_04, CATS2D_05_PL,
Mor04V, RDF080m, GATS6m, GATS7p be molecular descriptor；DLS_04 indicates that quasi-medicated property index, RDF080m indicate atom
The radial distribution function of quality weighting, GATS6m, GATS7p are respectively to indicate the Geary of quality weighting, polarizability weighting from phase
Index is closed, CATS2D_05_PL indicates molecule oleophylic lipophilic characteristics, Mor04VIndicate weight based on atom Van der waals volumes three
Tie up molecular structure.
Described molecular descriptor DLS_04, CATS2D_05_PL, Mor04V, RDF080m, GATS6m, GATS7p by with
Lower step obtains:
The molecular structure of OPFRs is optimized, Molecular structure descriptor is calculated using Dragon software, by gradually returning
Return to obtain 9 descriptors；
1) firstly, establishing the partial least square model comprising 9 variables, corresponding variance of dependent variable ratio Q is obtained2 CUM；
2) then, each descriptor is successively rejected from partial least square model, obtains a series of including 8 descriptors
Partial least square model and corresponding Q2 CUM, compare Q2 CUMThe size of value and threshold value, Q2 CUMValue is bigger, and the performance of model is got over
It is good；
3) Q then is selected in a series of resulting partial least square models of step 2)2 CUMSome mould being greater than the set value
Type continues to reject a variable i.e. descriptor, obtains new offset minimum binary equation and Q2 CUM, return step 3), traversal is all
8 partial least square models；
4) for each new offset minimum binary equation, different variables is successively rejected, a series of offset minimum binaries are obtained
Equation and Q2 CUMValue, the corresponding Q of more each offset minimum binary equation2 CUMValue, selects maximum Q2 CUMCorresponding DLS_04,
CATS2D_05_PL、Mor04V, RDF080m, GATS6m, GATS7p6 descriptors construct QSAR models, act on machine for explanation
System.
The molecular descriptor of the molecular structure according to software computational representation OPFRs to be measured is carried out by QSAR model
Assessment and prediction that OPFRs damages Biomimetic membrane the following steps are included:
The molecular structure of OPFRs to be measured is optimized, is described using the molecule that Dragon software obtains OPFRs to be measured
Symbol: DLS_04, CATS2D_05_PL, Mor04V,RDF080m,GATS6m,GATS7p；
Molecular descriptor is substituted into QSAR model, obtains the logarithm for the impedance value that OPFRs to be measured acts on Biomimetic membrane
logY；
Damage according to logY and molecular descriptor assessment and prediction OPFRs to Biomimetic membrane.
It is described to assess and predict damage of the OPFRs to Biomimetic membrane according to logY and molecular descriptor specifically:
The size of impedance value represents the potassium ferricyanide molecular probe in electrolyte and reaches the resistance being subject to when gold electrode surfaces
Size；LogY value is smaller, and the resistance that is subject to is smaller when molecular probe reaches gold electrode surfaces, the easier intrusion cell membrane of compound
Internal layer, the integrality of disrupting biofilm, so that other compounds are easier to cause body injury into film；LogY value is bigger, molecule
It is bigger that probe reaches the resistance being subject to when gold electrode surfaces, it is easier to stronger dipole-occur with the large biological molecule on film and lure
The effect of conductive coupling pole generates interaction with receptor protein, interferes signal transmitting 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:
Firstly, DLS_04 and GATS7p are the key factors for influencing OPFRs and membrane interaction:
DLS_04 value is bigger, contained in molecule replace functional group space structure and steric hindrance it is smaller, measurement it is film modified
Electrode impedance value it is smaller, compound is easier to interact with biosystem, invade cell film inner layer, disrupting biofilm
Integrality so that other compounds be easier to enter film cause body injury；
GATS7p value is bigger, and atom polarization ability is stronger, and the ability for obtaining dipole is also stronger, the film modified electricity of measurement
Pole impedance value is bigger, it is easier to stronger dipole-induced dipole occur with the large biological molecule on film and act on, to gather on film
Collection；Replace in molecule containing halogen and the electronegativity of the functional group of alkoxy substitution is stronger, it is easier to generate phase with receptor protein
Signal transmitting and related pathways on film are interfered in interaction；
Secondly, CATS2D_05_PL, the three-dimensional arrangement of atom also influences the phase interaction of OPFRs and biomembrane with space structure
With.
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 studies OPFRs to the micromechanism of membrane damage by building QSAR model, comments for the ecological risk of OPFRs
Offer basic data is provided.It is biological to simulation that the QSAR model that the present invention constructs accurately can easily evaluate OPFRs in application domain
The damage of film, the application domain of model include alkyl phosphate, alkoxy phosphate, halogenated alkyl phosphate and aryl phosphate ester etc.
16 kinds of OPFRs of 4 class different substituents.The QSAR model of foundation is simple and efficient, easy to operate, application domain is wide, can save reality
A large amount of manpower and material resources required for test tries, provide basic data for the risk assessment and marine monitoring of OPFRs.
Method of the invention only needs the descriptor of computational representation compound structure, can be simple and direct accurate by QSAR model
Ground judges its damage to Biomimetic membrane.
Detailed description of the invention
Fig. 1 is flow chart of the invention；
Fig. 2 is the equivalent circuit diagram for being fitted AC impedance modal data；
Fig. 3 is the measured value of logY and the fitted figure of predicted value；
Fig. 4 is the Euclidean distance figure for characterizing application domain；
Fig. 5 is the Williams figure for characterizing application domain.
Specific embodiment
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 OPFRs effects by electrochemical AC impedance method
Value.QSAR model is established using successive Regression and Partial Least Squares (PLS), illustrates OPFRs to the microcosmic work of membrane damage
With mechanism, damage 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 constructs QSAR model evaluation and predicts damage of the OPFRs to film.
The Biomimetic membrane model is the phospholipid bilayer life constructed by " frost-smearing " method in gold electrode surfaces
Object film.Firstly, 2- dipalmitoyl-glycerol -3- phosphoric acid mercaptoethanol (DPPTE) molecule is with treated, gold electrode passes through " Au-S "
Covalent bond forms monofilm；Phospholipid bilayer is then gone out in single layer film surface addition DPPC layer building 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 software, table is calculated
4885 descriptors for levying molecular structure choose descriptor by method of gradual regression, establish QSAR mould using Partial Least Squares
Type.
The QSAR model are as follows:
LogY=-1.82 × DLS_04-4.35 × 10-2CATS2D_05_PL+1.22×10-1Mor04V-9.33×10- 3RDF080m-4.80×10-1GATS6m+3.00×10-1GATS7p+1.70
N=16, R2 adj=0.881, F=119.45, SE=0.114, p < 0.001 (95% confidence interval), R2 X=
0.735, R2 Y=0.905, Q2 CUM=0.778, RMSE=0.110
In QSAR model, the quasi-medicated property index (DLS_04) and polarizability (GATS7p) of compound are to influence OPFRs
With the key factor of membrane interaction.DLS_04 value is bigger, replaces the space structure of functional group and steric hindrance to get over contained in molecule
Small, the film modified electrode impedance value (logY) of measurement is bigger, and compound is easier to interact with biosystem, intrusion
Cell film inner layer, the integrality of disrupting biofilm, so that other compounds are easier to cause body injury into film.GATS7p value is got over
Greatly, atom polarization ability is stronger, and the ability for obtaining dipole is also stronger, and the film modified electrode impedance value (logY) of measurement is more
It is small, it is easier to stronger dipole-induced dipole occur with the large biological molecule on film and act on, to assemble on film.In molecule
Replace containing halogen and the electronegativity of the functional group of alkoxy substitution is stronger, it is easier to generate interaction with receptor protein, it does
Disturb signal transmitting and the related pathways on film.Secondly, the oleophylic lipophilicity of compound, the three-dimensional arrangement and space structure of atom
It will affect 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 model, the mechanism of action damaged for analyzing OPFRs to film modified electrode mention for OPFRs ecological risk assessment and management
Data for reference.As shown in Figure 1, including the following steps:
(1) building of gold electrode surfaces supported bilayer lipid membrane
3000 mesh sand paper of gold electrode are polished, then gold electrode is polished with chamois leather (alumina powder and water), will polish
It is cleaned in the dehydrated alcohol of gold electrode afterwards and ultrapure water, the electrode after cleaning is placed in the mixed solution (concentrated sulfuric acid-mistake now matched
Hydrogen oxide volume ratio is impregnates 3min in 3:1), to remove electrode surface impurity.Electrode ultrapure water is taken out, after flushing
Electrode be connected to electrochemical workstation, use the sulfuric acid solution of 0.1mol/L as electrolyte, pass through cyclic voltammetry (CV)
Electric potential scanning is carried out, further to remove the impurity of electrode surface.0~1.6V of potential region, scanning speed 100mV/s, scanning
It 20 weeks, is cleaned, is dried up spare using ultrapure water after the completion of scanning.
DPPTE powder is dissolved in dehydrated alcohol, 2mmol/L DPPTE solution is configured to.DPPC powder is dissolved in
In n-decane, the DPPC n-decane solution that concentration is 20mg/mL is made.The anhydrous second of 0.5mL DPPTE is added into 1.5mL EP
Above-mentioned spare gold electrode is immersed DPPTE solution 16h, DPPTE molecule and passes through the sulfydryl on head and golden covalent bond by alcoholic solution
" Au-S " key is formed, forms monofilm in naked gold electrode surface self-organization.After electrode takes out, with washes of absolute alcohol 2min, with
The DPPTE molecule for removing electrode surface Non-covalent binding, is cleaned with ultrapure water later, after drying, 10 μ L is added dropwise to its surface and match
The DPPC solution made after being first placed in about 10min at room temperature, then in -20 DEG C of refrigerators placement about 30min, waves n-decane solvent
Hair.Electrode is taken out after solvent volatilization, about 15min is placed at room temperature, after solvent volatilizees completely, gold electrode is placed in
2h is impregnated in 0.1mol/L KCl solution, DPPC molecule is under hydrophilic and hydrophobic forces collective effect in DPPTE monofilm
Surface spontaneously forms second layer immobilized artificial membrane, as 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 detect
Membrane structure variation.This experiment uses CHI 760D electrochemical workstation, carries out electrification to Biomimetic membrane by three-electrode system
Learn detection.Electrolyte is 0.1mol/L potassium chloride, 0.1mol/L PBS and the 5mmol/L potassium ferricyanide 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 0.01Hz~100kHz, signal amplitude 5mV, measures impedance data, uses electrochemical workstation
Included Software on Drawing electrochemical impedance spectrogram, as shown in Fig. 2, the experimental result of EIS is simulated by 3.1 Software on Drawing of Zview
Equivalent circuit diagram carries out data fitting.Rs indicates that bath resistance, Rm indicate phospholipid bilayer film resistance, and Qm indicates normal phase bit
Part.
(3) building of data set
The two-dimensional molecular structure of 16 kinds of typical case OPFRs (table 1) is drawn by ChemDraw Ultra, uses Chem3D later
The minimizing energy method (minimum RMS gradient is 0.001) of Ultra software tentatively optimizes the molecular structure of model compound,
Obtain minimum energy configuration.Destination file is inputted into Dragon software (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) building of QSAR model
Using the impedance value logY of the lower double-deck film modified gold electrode of 16 kinds of typical OPFRs effects as QSAR model because
Variable.4885 initial molecular descriptors are subjected to primary dcreening operation by stepwise regression analysis, 9 descriptors is obtained, is respectively
DLS_04、CATS2D_05_PL、Mor04V,RDF080m,GATS6m,GATS7p,SPH,MATS8V,RDF065e.Using Simca
Model is established in offset minimum binary (PLS) recurrence in software.PLS ingredient is determined using Leave-group-out cross validation, it is first
First, the PLS model comprising 9 variables is established, corresponding variance of dependent variable ratio Q is calculated in software2 CUM, then retouched each
State symbol successively rejected from model successively obtain it is a series of include 8 descriptors new model and corresponding Q2 CUM, then heavy
Multiple aforesaid operations process, rejects a variable every time, obtains corresponding offset minimum binary equation and Q2 CUM, more each model pair
The Q answered2 CUMValue, selects maximum Q2 CUMCorresponding DLS_04, CATS2D_05_PL, Mor04V、RDF080m、GATS6m、
6 descriptors of GATS7p construct QSAR model, for explaining the QSAR model of mechanism of action.Q2 CUMIt is worth bigger, the performance of model
It is better, it is considered that Q2 CUM>=0.5, model has good conspicuousness and predictive ability；Screening obtains descriptor in QSAR model
Essential information such as table 2.
Table 2
aThe quasi-medicated property structure index of old et al. the modification of DLS_04
bCATS2D_05_PL describes compound oleophylic lipophilicity
cMor04VIndicate the three-dimensional molecular structure that signal 04 is weighted based on atom Van der waals volumes
dRDF080m indicates the radial distribution function weighted by atomic mass
eGATS6m indicates the Geary auto-correlation weighted by atomic mass
fGATS7p indicates the Geary auto-correlation weighted by atomic polarizability
The expression formula of QSAR model are as follows:
LogY=-1.82 × DLS_04-4.35 × 10-2CATS2D_05_PL+1.22×10-1Mor04V-9.33×10- 3RDF080m-4.80×10-1GATS6m+3.00×10-1GATS7p+1.70
N=16, R2 adj=0.881, R2 X=0.735, R2 Y=0.905, Q2 CUM=0.719, RMSE=0.110
In a model, logY is expressed as the function of 6 descriptor variables, training set data n=16.The statistics of model testing
F=119.45 is measured, standard error SE=0.114, significance p < 0.001 (95% confidence interval), referendum determines coefficients R2 adj
=0.881, multiple correlation coefficient square R2 X=0.735, multiple correlation coefficient square R2 Y=0.905, mean square deviation error RMSE=
0.110 shows that model has the good goodness of fit, cross validation coefficient Q2 CUM=0.719 shows that model has good robustness,
The R of model2 YAnd Q2 CUMDifference show that model does not have over-fitting less than 0.3.The expression of table 3, the reality of the logY of 16 kinds of typical OPFRs
Measured value and predicted value, Fig. 3 expression, the measured value of the logY of 16 kinds of typical OPFRs and the fitting result of predicted value.Using training
Collection/verifying collection Split Method testing model robustness, cross-validation coefficient Q2 IN=0.778, it is steady well to illustrate that model has
Strong property.Diagnostic factro variance inflation factor VIF<10 between each variable, tolerance tolerance>0.1, state indices Condition
Index < 30 illustrate that independently there is no serious multicollinearities between each independent variable.Table 3 is 16 kinds of typical OPFRs'
The measured value and predicted value of logY.
Table 3
In QSAR model, logY is the double-deck film modified gold electrode value of relative impedance, and DLS_04 describes compounds pharmacological property
Index, this index consider a series of property, including when molecule formation hydrogen bond, the quantity of hydrogen bond donor and receptor, lipophilic
Property and index of unsaturation etc.；CATS2D_05_PL describes compound oleophylic lipophilic property；Mor04VDescription is by using difference
Angular scattering function calculate the summations of all atom Van der waals volumes, indicate the three-dimensional arrangement of atom to molecular size and shape
Influence；RDF080m describes the radial distribution function weighted by atomic mass, for indicating in specific three-D space structure
Specific information；GATS6m describes the 2D auto-correlation function weighted by quality, for indicating that specific molecular structure, autocorrelation are got over
It is strong then GATS6m value is smaller；GATS7p describes the atom polarization ability of identical topology distance.
Such as table 4, importance index (VIP) value is projected according to descriptor analysis shows, the quasi-medicated property index (DLS_ of compound
04) and polarizability (GATS7p) be influence OPFRs and film effect key factor.DLS_04 value 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 easier to cause body injury into film.GATS7p value 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 effect, to assemble on film.Replace in molecule containing halogen and the electronegativity of the functional group of alkoxy substitution is got over
By force, easier to generate interaction with receptor protein, interfere signal transmitting and related pathways on film.In addition, the oleophylic of chemical combination
Lipophilicity, the three-dimensional arrangement and space structure of atom also will affect the interaction of OPFRs and film.Table 4 is to retouch in QSAR model
State symbol projection importance index (VIP) value.
Table 4
(5) QSAR model application domain characterizes
The application domain of QSAR model is characterized by Euclidean distance figure and Williams figure, such as Fig. 4, Euclid
Distance map is by Ambit discovery v0.04 Software on Drawing, and Euclidean distance is less than 1.29, and the compound of training set is all
In model application domain, illustrate that the training set of model has good representativeness.Such as Fig. 5, the standard of Williams figure compound
For residual error all within (- 2.5,2.5), the lever value of compound is respectively less than warning value 1.31, illustrates that model does not have outlier.Pass through
Application domain is characterized, do not find outlier and is misvalued a little, it is ensured that modal analysis results are credible.
In OPFRs data set constructed by the present invention, the OPFRs that replaces including the cyclosubstituted OPFRs of 8 benzene, 2 chlorine, 5
A OPFRs replaced containing alkyl-substituted OPFRs and 1 alkoxy.
Embodiment 1
Tri-2-ethylhexyl phosphate (TEHP): use Williams figure method be calculated its lever value hi for 0.521 <
H* (early warning value)=1.31, residual (SE)=1.40 < 2.50 illustrate this compound in QSAR model application domain.Experiment
The TEHP impedance value of measurement be 0.673 compared to be all alkyl-substituted tributyl phosphate (TBP)-impedance value 0.626 is bright
It is aobvious to increase, Analysis on Mechanism is carried out according to QSAR model, TEHP is due to the biggish branched alkyl substituent of space structure, so that characterization atom
The descriptor Mor04 of spatial arrangement and three-dimensional structureVNumerical value increase to 1.95 from 0.147, quasi-medicated property index reduces from 0.80
To 0.30, the GATS7p for characterizing atomic polarizability increases to 1.10 from 0.557, so that compound is easier to be inserted into or adhere to
In film outer surface, increase the electrode impedance value of film, interferes signal transmitting and related pathways on film.
Embodiment 2
Tricresyl phosphate (2- chloroethyl) ester (TCEP): use Williams figure method that its lever value hi is calculated as 0.218 < h*
(early warning value)=1.31, residual (SE)=- 0.484 > -2.50 illustrate this compound in QSAR model application domain.TBP
The alkyl substitution of carbochain end become halogen (Cl) substitution, the TCEP impedance value that the halogen (Cl) of measuring replaces be for
0.0173 obviously increases compared to the impedance value 0.626 of alkyl-substituted tributyl phosphate (TBP), carries out machine according to QSAR model
Reason analysis, TCEP cause compound electronegativity to enhance, so that quasi-medicated property index reduces from 3 due to replacing functional group containing halogen
To 0, the GATS7p for characterizing atomic polarizability increases to 0.674 from 0.557, is easy to generate active force insertion with receptor protein molecule
Or it is attached to film outer surface, to increase film modified electrode impedance value, interfere signal transmitting and related pathways on film.
Embodiment 3
Tricresyl phosphate (TMTP): use Williams figure method that its lever value hi is calculated as 0.678 < h* (early warning
Value)=1.31, residual (SE)=- 0.911 > -2.50 illustrate this compound in QSAR model application domain.Measuring
TMTP impedance value be for -0.406 compared to be all the cyclosubstituted three p-toluenesuifonic acids ester (TPTP) of virtue impedance value 0.577 it is bright
It is aobvious to increase, Analysis on Mechanism is carried out according to QSAR model, aromatic ring replaces and TMTP, since the position of substitution of the methyl on phenyl ring is by right
Meta position is arrived in position, so that the steric hindrance of compound is reduced, the descriptor Mor04 of characterization atomic space arrangement and three-dimensional structureV's
Numerical value is reduced to -0.257 from 0.797, and the GATS7p for characterizing atomic polarizability is reduced to 0.431 from 1.87, characterizes fat-soluble
CATS2D_05_PL increases to 6 from 3, reduces the electrode impedance value of film, and compound is easier to the internal layer of intrusion film, changes film knot
Structure destroys the integrality of film.
Claims (9)
1. the method that assessment and prediction organophosphate ester flame retardant damage Biomimetic membrane, it is characterised in that:
QSAR model is constructed 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 model
The assessment and prediction of quasi- biomembrane damage；
The QSAR model is as follows:
LogY=-1.82 × DLS_04-4.35 × 10-2CATS2D_05_PL+1.22×10-1Mor04V-9.33×10- 3RDF080m-4.80×10-1GATS6m+3.00×10-1GATS7p+1.70
Wherein, logY is the logarithm for the impedance value that OPFRs acts on Biomimetic membrane, DLS_04, CATS2D_05_PL, Mor04V、
RDF080m, GATS6m, GATS7p are molecular descriptor；DLS_04 indicates that quasi-medicated property index, RDF080m indicate that atomic mass adds
The radial distribution function of power, GATS6m, GATS7p are respectively the Geary autocorrelation exponent for indicating quality weighting, polarizability weighting,
CATS2D_05_PL indicates molecule oleophylic lipophilic characteristics, Mor04VIndicate the three-dimensional molecular knot weighted based on atom Van der waals volumes
Structure.
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, the OPFRs that replaces including the cyclosubstituted OPFRs of 8 benzene, 2 chlorine, 5 taken containing alkyl
The OPFRs that OPFRs and 1 alkoxy in generation replaces.
5. the method that assessment according to claim 1 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, described molecular descriptor DLS_04, CATS2D_05_PL, Mor04V, RDF080m, GATS6m, GATS7p by with
Lower step obtains:
The molecular structure of OPFRs is optimized, Molecular structure descriptor is calculated using Dragon software, is obtained by successive Regression
To 9 descriptors；
1) firstly, establishing the partial least square model comprising 9 variables, corresponding variance of dependent variable ratio Q is obtained2 CUM；
2) then, each descriptor is successively rejected from partial least square model, obtains a series of including the inclined of 8 descriptors
Least square model and corresponding Q2 CUM, compare Q2 CUMThe size of value and threshold value, Q2 CUMValue is bigger, and the performance of model is better；
3) Q then is selected in a series of resulting partial least square models of step 2)2 CUMSome model being greater than the set value continues
A variable i.e. descriptor is rejected, new offset minimum binary equation and Q is obtained2 CUM, return step 3), it is inclined to traverse all 8
Least square model；
4) for each new offset minimum binary equation, different variables is successively rejected, obtains a series of offset minimum binary equations
And Q2CUM value, the corresponding Q of more each offset minimum binary equation2 CUMValue, selects maximum Q2 CUMCorresponding DLS_04,
CATS2D_05_PL、Mor04V, totally 6 descriptors construct QSAR model by RDF080m, GATS6m, GATS7p, acted on for explanation
Mechanism.
6. 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 model
Assessment and prediction that OPFRs damages Biomimetic membrane the following steps are included:
The molecular structure of OPFRs to be measured is optimized, obtains the molecular descriptor of OPFRs to be measured using Dragon software:
DLS_04、CATS2D_05_PL、Mor04V,RDF080m,GATS6m,GATS7p；
Molecular descriptor is substituted into QSAR model, obtains the logarithm logY for the impedance value that OPFRs to be measured acts on Biomimetic membrane；
Damage according to logY and molecular descriptor assessment and prediction OPFRs to Biomimetic membrane.
7. the method that assessment according to claim 6 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, it is described to assess and predict damage of the OPFRs to Biomimetic membrane according to logY and molecular descriptor specifically:
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；
LogY value is smaller, and 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 easier to cause body injury into film；LogY value 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 transmitting and related pathways on film.
8. the method that assessment according to claim 6 and prediction organophosphate ester flame retardant damage Biomimetic membrane,
It is characterized in that, described to assess and predict that OPFRs is specific as follows to the damage of Biomimetic membrane according to logarithm and molecular descriptor:
Firstly, DLS_04 and GATS7p are the key factors for influencing OPFRs and membrane interaction:
DLS_04 value 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 easier to cause body injury into film；
GATS7p value 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；
Replace in molecule containing halogen and the electronegativity of the functional group of alkoxy substitution is stronger, it is easier to generate phase interaction with receptor protein
With signal transmitting and related pathways on interference film；
Secondly, CATS2D_05_PL, the three-dimensional arrangement and space structure of atom also influence the interaction of OPFRs and biomembrane.
9. the method that assessment according to claim 6 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
One of.
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