CN1119645C - Phase/light intensity composite type bio-molecular interaction real-time detection method and its system - Google Patents
Phase/light intensity composite type bio-molecular interaction real-time detection method and its system Download PDFInfo
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Abstract
The present invention relates to a phase/light intensity composite biologic molecular interaction real-time detection method and a system thereof, which belongs to the technical field of biology. The system is composed of a biologic sensing unit, a sample transmission unit and a signal processing unit. The present invention is characterized in that a splitter for optical elements divides laser sent out by a laser into two paths, one path is used for detecting the light intensity variation, and the other path is used for detecting the phase variation, so the phase/ light intensity composite biologic molecular interaction real-time detection is realized, and various kinds of information, particularly the relationship between the biologic molecular structure and the function, the biologic molecular functional characteristics, etc. are obtained. The present invention has the advantages of high sensitivity, simple structure and easy realization.
Description
Technical field the invention belongs to biological technical field, particularly is used for the method for the interaction situation between two above biomolecule such as protein-protein, acceptor-part, nucleic acid-protein, biology-protein and the nucleic acid-nucleic acid etc. that realize to detect and with the equipment of this method.
Background technology is utilized surface plasma body resonant vibration (Surface Plasmon Resonance, be called for short SPR) principle, make up the real-time check and analysis of bio-molecular interaction system, realization is to the monitoring and the analysis of bio-molecular interaction, two technological approaches are arranged: a light intensity detection method that is based on the SPR principle, cause when promptly interacting that catoptrical light intensity changes, and obtains relevant biological information by detectable biomolecule.The BIAtite and the Biacore 1000 of Sweden Pharmacia Bioisystech Co., Ltd (Pharmacia Biatech), 2000,3000 series of products such as grade adopt this method exactly, it detects principle as shown in Figure 1, the laser that is sent by semiconductor laser 1 sees through prism 2, has a snack layer 3 (its effect is the air gap of eliminating between prism 2 and the glass substrate 4) and a glass substrate 4 with critical angle, be mapped on the interface of glass substrate 4 and transparent organism sensing layer 6, produce reflection, catoptrical intensity is substantially equal to the incident light intensity.But, after the golden film 5 that plating one deck 50nm is thick on glass substrate 4, the part energy of incident light will with the free electron effect on golden film surface, evoke resonance, decay along the resonance wave direction of propagation, thereby cause that catoptrical intensity weakens greatly on a specific angle direction, even disappear that the disappear incident angle in time of reflected light is called resonance angle.Resonance angle changes with the refractive index on sensing layer surface, refractive index is accompanyed or follow biomolecule action situation fixing on biomolecule in the sample that flows through in the sample cell 7 and the sensing layer again and is changed, and promptly power, what and the speed with bio-molecular interaction changes.Reflected light is received by photodetector 8, converts electric signal to, then reads in processing by computing machine, can therefrom obtain relevant biological information.Another is based on the phase-detection method of SPR principle, and the catoptrical phase change that causes when promptly interacting by detectable biomolecule is obtained relevant biological information.(application number: be exactly to adopt this method 99107780.6), it detects principle as shown in Figure 2 in the inventor's " biomolecular interaction real-time phase detection analysis method and system thereof "." the tail light " that sent by transverse zeeman laser 9 is received by photodetector 18 by analyzer 19 backs, converts electric signal to, as reference signal input differential digital phase demodulation phase place card 20.Inject from a central plane of Dove prism 10 by the laser that the transverse zeeman laser output terminal sends, be mapped on the interface of bottom surface and golden film 11, the gold film covers coupling connection layer 12 and ligand molecular 13 for 11 times, incident light is from this boundary reflection, pass through analyzer 16 again after seeing through another central plane, received by photodetector 17, convert electric signal to, as measuring-signal input differential digital phase demodulation phase place card 20.The reference signal and the measuring-signal of 20 pairs of inputs of phase place card carry out the differential digital phase demodulation, obtain phase data, are read in by computing machine 21, carry out processing and analysis based on phase place, obtain relevant biological information.
Above-mentioned these two kinds of methods can be carried out the intermolecular interaction of detection of biological, between analyzing molecules how combination with separate, how much intensity what and speed is, the dystopy of whether having living space effect etc.The light intensity detection method is by surveying the situation of change that intensity variations reflects the sensing layer surface refractive index, be power, what and the speed situation of bio-molecular interaction, variations in refractive index is corresponding with the effect situation, simple in structure, but light source intensity can fluctuate, and light intensity is a direct current signal, treatment circuit has dc shift, they all influence measuring accuracy, and resolution is limited, improve resolution and can cause circuit too complicated.The phase-detection method is to change the change in optical path length that reflects that the sensing layer surface causes by detecting phase, i.e. the power of bio-molecular interaction, and the situation of what and speed, light path (phase place) variation is corresponding with the effect situation.Simultaneously, phase signal is an AC signal, and is more stable than the former., all there is deficiency in these two kinds of methods, and the former is to the power of combination and change the most responsively, and the latter is more responsive to the speed of combination and what.Therefore, when facing different bio-molecular interactions, two kinds of diverse ways all might be lost some biological informations highly significant.
Summary of the invention the objective of the invention is to overcome the limitation of above-mentioned every kind of method, a kind of new bio-molecular interaction real-time detection method is provided and is used for the bio-molecular interaction real-time detecting system of this method.Make it have the advantage of above-mentioned two kinds of methods simultaneously, promptly not only can change by the light intensity of detection of reflected light, and can be by the phase change of detection of reflected light, obtain the multiple information between the biomolecule thus, the more important thing is the structure and relation between the function and the functional character thereof etc. that obtain biomolecule.And have highly sensitive, simple in structure, the easy advantage that realizes.
The present invention proposes a kind of bio-molecular interaction real-time detection method that adopts phase/light intensity composite type to measure, and may further comprise the steps:
1) " the tail light " that is seen through by transverse zeeman laser total reflection end by being received by photodetector behind the analyzer, converts electric signal to, as the reference signal input differential digital phase demodulation phase place card of phase-detection;
2) laser that is sent by the transverse zeeman laser output terminal is injected from a central plane of isosceles trapezoid/Tp, on the interface of the bottom surface that is mapped to this prism and the golden film that is coated with the bio-sensing layer that is plated in its bottom surface, incident light sees through another central plane of this prism behind this boundary reflection, be mapped on the beam divider, part reflection, another part sees through;
3) reflecting part is received by photodetector, convert electric signal to, as light intensity detection method signal input preposing signal process circuit 24, permeation parts is received by photodetector after by analyzer, convert electric signal to, as the measuring-signal input differential digital phase demodulation phase place card of phase-detection;
4) said preposing signal process circuit is to handling as the electric signal of light intensity detection method input, obtain the digital optical intensity delta data, said differential digital phase demodulation phase place card to the input measurement with handle with reference to two paths of signals, obtain the digit phase delta data, two kinds of data are read in by computing machine, software with establishment in advance carries out processing and analysis based on light intensity and phase place respectively, and two kinds of data are carried out analysis-by-synthesis and comparison.
The present invention proposes the real-time check and analysis of a kind of phase/light intensity composite type bio-molecular interaction system, form by bio-sensing unit, defeated sample unit and signal processing unit three parts, said bio-sensing unit by isosceles trapezoid/Tp and be plated in its bottom surface golden film, cover the bio-sensing layer on the golden film, and the core component that places the sample cell formation sensor it under; It is characterized in that, said signal processing unit by differential digital phase demodulation phase place card, preposing signal process circuit, computing machine and be stored in wherein in advance the establishment software form; Said defeated sample unit is made up of retaining valve, dip can and defeated sample device, and dip can links to each other by retaining valve with defeated sample device, and defeated sample device links to each other by the sample cell of retaining valve with the bio-sensing unit; Place the transverse zeeman laser of this prism one side and be arranged on the analyzer of the total reflection end of this laser instrument, detector constitutes reference arm, place the beam divider on the output optical axis of this prism opposite side, place an analyzer and the photodetector on the transmitted light path of beam divider and place another photodetector on the reflected light path of beam divider to constitute gage beam, the said light that is mapped on the beam divider, being detected device after the part reflection receives, convert the photon flux method detection signal to, another part sees through, behind analyzer, received, convert the measuring-signal of phase-detection to by photodetector.
The frequency difference of the said transverse zeeman laser of the present invention can be between 30～500KHz, the golden film thickness of said isosceles trapezoid/Tp bottom surface plating can be between 30～50nm, said bio-sensing layer can by cover successively Covalent Immobilization on this gold film have a liking for the aqueous high molecular base layer and the part bio-molecule layer constitutes; Analyzer between said isosceles trapezoid/Tp and the photodetector, analyzer between transverse zeeman laser and the photodetector can be installed on the position with optical axis angle at 45, said beam divider is the key element that phase/light intensity composite type bio-molecular interaction detects in real time, it is divided into two-way with the light that laser instrument sends, realize that one the tunnel detects the light intensity variation, and another road detected phase changes, and places between reflected light path isosceles trapezoid/Tp and the analyzer to become on the position of 22.5 ° of angles with optical axis.
Differential digital phase demodulation phase place card in the said system is at the scene in the programmable array device, a circuit board of realizing by programming; The circuit board that said preposing signal process circuit is made up of 12 A/D of a slice and the two-way memory bank device of a slice; These two circuit boards insert in the universal slot of computing machine.
Method of the present invention and the principle of work that is used for the system of this method thereof are: " the tail light " that seen through by the fully reflecting surface of transverse zeeman laser is received by photodetector behind analyzer, convert electric signal to, as the reference signal input differential digital phase demodulation phase place card of phase-detection.Injected from a central plane of Dove prism by the laser that the output terminal of transverse zeeman laser sends, be mapped on the surface of bottom surface and golden film, cover coupling connection layer on the golden film, coupling connection layer is gone up coupling connection part.Incident light is from this boundary reflection, seeing through another central plane is mapped on the beam divider, part reflection back is received by photodetector, convert electric signal to, the input preposing signal process circuit obtains the digital optical intensity delta data after treatment, another part sees through beam divider, received by photodetector through behind the analyzer, convert electric signal to, as the measuring-signal input differential digital phase demodulation phase place card of phase-detection.The phase place card to the input measurement with carry out the differential digital phase demodulation with reference to two paths of signals, obtain the digit phase difference data.Sample flows through from sample cell, and acceptor combines with part, in conjunction with intensity, what and speed differ, the digit phase difference data that digital optical intensity delta data that preposing signal process circuit obtains and phase place card obtain becomes thereupon.Computer real-time reads the light intensity delta data and read phase data from the phase place card from preposing signal process circuit, can carry out data processing and analysis respectively based on light intensity and phase place, two kinds of data are carried out analysis-by-synthesis and comparison, obtain the various information of bio-molecular interaction, even also may find new information.
Outstanding feature of the present invention is:
One, it causes in the time of occurring in the lip-deep bio-molecular interaction of golden film by detection simultaneously that catoptrical phase place and light intensity change, obtain the digit phase difference data through phase discrimination processing, with behind preposing signal process circuit, obtain digital light intensity delta data, read in this two kinds of data by computing machine again.
Its two, the present invention carries out Treatment Analysis based on phase place and light intensity first simultaneously with the software of establishment in advance; The more important thing is these two kinds of data are carried out analysis-by-synthesis and comparison, obtain than more comprehensively relevant biological information.For example compare the slope and the height of the rising or the decline of light intensity and phase change curve, obtain the space coupling and connect structure variation and signal conduction feature, especially obtain structure, the relation between the function and the functional character thereof etc. of biomolecule.
They are three years old, the present invention only adopts an optical element beam divider, the light that laser instrument is sent is divided into two-way, one the tunnel detects light intensity changes, and another road detected phase changes, and has realized that phase/light intensity composite type bio-molecular interaction detects in real time, has highly sensitive, simple in structure, the easy advantage that realizes.
They are four years old, the present invention can realize the interaction of real-time detection of biological molecule, obtain between biomolecule how combination and dissociate, in conjunction with and the intensity and the velocity magnitude of dissociating, whether there are dwellings such as space dystopy effect, and can carry out analysis-by-synthesis, obtain the space coupling and connect the structure variation, many information such as signal conduction feature, antigen decision family's graphic analysis and structure-function relationship.
Description of drawings
Fig. 1 is that existing a kind of light intensity detection method bio-molecular interaction detects principle schematic.
Fig. 2 is that known a kind of phase-detection method bio-molecular interaction detects principle schematic.
Fig. 3 is a phase/light intensity composite type bio-molecular interaction detection system synoptic diagram of the present invention.
Fig. 4 carries out the process flow diagram of phase place and light intensity signal analysis-by-synthesis for computing machine of the present invention.
Embodiment is below in conjunction with accompanying drawing, and the embodiment of the real-time check and analysis of the bio-molecular interaction system that adopts SPR phase/light intensity detection method of the present invention is described.
Present embodiment is made up of the SPR bio-sensing unit, sampling unit and the signal processing unit three parts that detect based on phase/light intensity, as shown in Figure 3.Wherein, phase/light intensity detects SPR bio-sensing unit and comprises: transverse zeeman laser 9, analyzer 16,19, detector 17,18,23, beam divider 22, by Dove prism 10 be plated in golden film 11 on its bottom surface, cover coupling connection layer 12 on the golden film 11 and coupling and be associated in ligand 13 on the coupling connection layer, and the core component that places the sensor of sample cell 15 formations under it, defeated sample unit comprises: by the dip can 25 that retaining valve 26,28 links to each other, and defeated sample device 27; Signal processing unit comprises: preposing signal process circuit 24, differential digital phase demodulation phase place card 20 and computing machine 21.
The principle of work of present embodiment is: dip can 25 is selected required sample under computer control, opens valve 26.Then, defeated sample device 27 sucks sample under the control of computing machine.After sample sucked, valve 26 was closed, and valve 28 is opened, and defeated sample device 27 is not slowly with sample delivery (dip can 25 and defeated sample device 27 are given unnecessary details here as the inventor's the last content of applying for a patent) in sample cell.The laser that is sent by transverse zeeman laser 9 output terminals sees through a central plane of Dove prism 10, and on the bottom surface that is mapped to Dove prism 10 and the interface of golden film 11, and from this boundary reflection, another central plane through Dove prism 10 is mapped on the beam divider 22.An incident light part is received by photodetector 23 after beam divider 22 reflections, converts electric signal to, and another part sees through beam divider 22, is received by photodetector 17 by analyzer 16 backs again, converts electric signal to.When sample flow is crossed sample cell 15, acceptor molecule 14 in the sample combines with ligand molecular 13 on the sensing layer, catoptrical light intensity and phase place all change, detector 23 is surveyed light intensity and is changed, input preposing signal process circuit 24 is handled in real time, obtain the digital optical intensity delta data, detector 17 detecting phases change, as the measuring-signal input differential digital phase demodulation phase place card 20 of phase-detection." the tail light " that seen through by the fully reflecting surface of transverse zeeman laser 9 is received by photodetector 18 behind analyzer 19, converts electric signal to, is input to differential digital phase demodulation phase place card 20 as the reference signal of phase-detection.Phase place card 20 is handled the measuring-signal and the reference signal that arrive simultaneously in real time, obtains the digit phase difference data.
1) computing machine reads the data of phase place and light intensity deal with data or corresponding curve;
2) compare association rate or rate of rise earlier;
3) follow the amplitude that compares equilibrium state or curve balance;
4) relatively free speed or curve descending slope again;
5) also want the analysis-by-synthesis comparative result;
6) provide pairing biological significance at last.
By analyzing, can obtain between more detailed biomolecule how combination and dissociate, in conjunction with what being with the intensity and the speed of dissociating, whether there is space dystopy effect, the structural change of space coupling connection, many biological informations such as signal conduction feature and structure-function relationship also may obtain undiscovered information, can be in order to instruct new exploration.
Claims (8)
1. phase/light intensity composite type bio-molecular interaction real-time detection method may further comprise the steps:
1) " the tail light " that is seen through by transverse zeeman laser (9) total reflection end is received by photodetector (18) by analyzer (19) back, converts electric signal to, as the reference signal input differential digital phase demodulation phase place card (20) of phase-detection;
2) laser that is sent by transverse zeeman laser (9) output terminal is injected from a central plane of isosceles trapezoid/Tp (10), on the interface of the bottom surface that is mapped to this prism and the golden film (11) that is coated with the bio-sensing layer that is plated in its bottom surface, incident light sees through another central plane of this prism behind this boundary reflection, be mapped on the beam divider, part reflection, another part sees through;
3) reflecting part is received by photodetector (23), convert electric signal to, as light intensity detection method signal input preposing signal process circuit (24), permeation parts is being received by photodetector (17) by analyzer (16) back, convert electric signal to, as the measuring-signal input differential digital phase demodulation phase place card (20) of phase-detection;
4) said preposing signal process circuit (24) is to handling as the electric signal of light intensity detection method input, obtain the digital optical intensity delta data, said differential digital phase demodulation phase place card (20) to the input measurement with handle with reference to two paths of signals, obtain the digit phase delta data, two kinds of data are read in by computing machine, software with establishment in advance carries out processing and analysis based on light intensity and phase place respectively, and two kinds of data are carried out analysis-by-synthesis and comparison.
2. the real-time check and analysis of phase/light intensity composite type bio-molecular interaction system, form by bio-sensing unit, defeated sample unit and signal processing unit three parts, said bio-sensing unit by isosceles trapezoid/Tp (10) and be plated in its bottom surface golden film (11), cover the bio-sensing layer on the golden film, and place sample cell (15) under it to constitute the core component of sensor; It is characterized in that, said signal processing unit by differential digital phase demodulation phase place card (20), preposing signal process circuit (24), computing machine (21) and be stored in wherein in advance the establishment software form; Said defeated sample unit is made up of retaining valve (26,28) dip cans (25) and defeated sample device (27), dip can (25) and defeated sample device (27) are by retaining valve 26) link to each other, defeated sample device (27) links to each other with the sample cell of bio-sensing unit by retaining valve (28); Place the transverse zeeman laser (9) of this prism one side and be arranged on the analyzer (19) of the total reflection end of this laser instrument, detector (18) constitutes reference arm, place the beam divider (22) on the output optical axis of this prism opposite side, place an analyzer (16) and the photodetector (17) on the transmitted light path of beam divider and place another photodetector (23) on the reflected light path of beam divider to constitute gage beam, the said light that is mapped on the beam divider, being detected device after the part reflection receives, convert the photon flux method detection signal to, another part sees through, behind analyzer, received, convert the measuring-signal of phase-detection to by photodetector.
3. check and analysis system as claimed in claim 2 is characterized in that the frequency difference of said transverse zeeman laser is between 30～500KHz.
4. check and analysis system as claimed in claim 2 is characterized in that, the golden film thickness of said isosceles trapezoid/Tp (10) bottom surface plating is between 30～50nm.
5. check and analysis system as claimed in claim 2 is characterized in that, said bio-sensing layer can by cover successively Covalent Immobilization on this gold film have a liking for the aqueous high molecular base layer and the part bio-molecule layer constitutes.
6. check and analysis system as claimed in claim 2, it is characterized in that, analyzer between said isosceles trapezoid/Tp (10) and the photodetector, the analyzer between transverse zeeman laser and the photodetector are installed on the position with optical axis angle at 45.
7. check and analysis system as claimed in claim 2 is characterized in that, said beam divider places between reflected light path isosceles trapezoid/Tp (10) and the analyzer to become on the position of 22.5 ° of angles with optical axis.
8. check and analysis system as claimed in claim 2 is characterized in that, the differential digital phase demodulation phase place card in the said system is at the scene in the programmable array device, a circuit board of realizing by programming; The circuit board that said preposing signal process circuit is made up of 12 A/D of a slice and the two-way memory bank device of a slice; These two circuit boards insert in the universal slot of computing machine.
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| CN106092967B (en) * | 2016-05-30 | 2019-03-01 | 清华大学深圳研究生院 | A kind of detection method and device of bio-molecular interaction |
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