CN102749441B - Imaging magnetic tweezers device, and system and method for integrating imaging magnetic tweezers device with single-molecule fluorescence technology - Google Patents
Imaging magnetic tweezers device, and system and method for integrating imaging magnetic tweezers device with single-molecule fluorescence technology Download PDFInfo
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- CN102749441B CN102749441B CN 201210232172 CN201210232172A CN102749441B CN 102749441 B CN102749441 B CN 102749441B CN 201210232172 CN201210232172 CN 201210232172 CN 201210232172 A CN201210232172 A CN 201210232172A CN 102749441 B CN102749441 B CN 102749441B
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Abstract
The invention discloses an imaging magnetic tweezers device, and a system and a method for integrating imaging magnetic tweezers device with a single-molecule fluorescence technology. The imaging magnetic tweezers device comprises a magnetic object lens with adjustable magnetic field gradient and magnetic field intensity, an illuminating light source and an electric coupling device. The magnetic object lens is combined with the illuminating light source and the electric coupling device to realize superparamagnetic microsphere imaging and conduct single-molecule mechanical control at the same time. On one hand, a magnetic tweezers experiment can be conduct, the magnetic tweezers device can be integrated with various single-molecule fluorescence technologies for application, not only can fluorescence signal detection be conducted to a sample, but also mechanical control can be conducted to the sample, and the fluorescence signal detection and the mechanical control are independent to each other and do not interfere with each other; and on the other hand, the imaging magnetic tweezers device can apply constraints to superparamagnetic microspheres in the sample, the Brownian fluctuation of a single-molecule connecting system can be effectively reduced, an integrated single-molecule fluorescence device can obtain staler fluorescence signals, and the experimental accuracy during single-molecule control measurement is improved.
Description
Technical field
The present invention relates to single molecule manipulation and the detection range of biomacromolecule, relate in particular to a kind of imaging magnetic tweezers and with the integrated system and method for single molecular fluorescence technology.
Background technology
The method that common unimolecule magnetic tweezer manipulation technology is taked magnet and corresponding charge coupled device are installed in the optical microphotograph lens device realizes single molecule manipulation, though this method is simple, measuring accuracy is not high.The single molecular fluorescence technology can realize the single-molecule detection of nanometer even inferior nanometer level, but it can't carry out controlled unimolecule mechanical meaurement.For biomacromolecule, we should measure the consequence of intermolecular interaction, survey the reason that causes these consequences again, this just guides us that the mechanics manipulation technology is incorporated in the single molecular fluorescence technology, application unimolecule mechanics manipulation technology reduces Blang's fluctuation of measuring system, utilize the single molecular fluorescence commercial measurement to obtain the higher fluorescence signal of stability simultaneously, thereby realize the combination that the unimolecule mechanics is handled and single molecular fluorescence is surveyed.
Concrete, in the unimolecule magnetic tweezer manipulation technology of classics, magnet and viewing objective lay respectively at the both sides of flat samples, and the operating distance between magnet-sample and the object lens-sample is very little, can't introduce other device under such space layout again and integrate, limit the integrated application of common magnetic tweezer and other unimolecule technology.
Summary of the invention
The present invention is directed to prior art and can't realize that the unimolecule mechanics is handled and the problem of the combination that single molecular fluorescence is surveyed, propose a kind of imaging magnetic tweezers and with the integrated system and method for single molecular fluorescence technology, can realize that the unimolecule mechanics of the integrated and inferior nano-precision of magnetic tweezer and single molecular fluorescence technology is handled and measured.
In order to address the above problem, the invention provides a kind of imaging magnetic tweezers, comprise magnetic object lens, lighting source and charge coupled device (CCD) that magnetic field gradient and magnetic field intensity are adjustable, described magnetic object lens and lighting source and CCD combination is carried out the unimolecule mechanics when realizing the super paramagnetic microsphere imaging and is handled.
Preferably, said apparatus has following characteristics:
Described magnetic object lens comprise object lens and are integrated in magnetic field gradient and the adjustable ring-shaped magnet of intensity of object lens head that described ring-shaped magnet is the magnetic tweezer.
Preferably, said apparatus has following characteristics:
The described ring-shaped magnet that is integrated in the object lens head comprises two blocks of ring-shaped magnets, is respectively front end magnet and rear end magnet, and described front end magnet is as the emergent pupil of described object lens; Described rear end magnet is enclosed within the object lens periphery, and its magnetic field and the stack of front end magnet are by sliding the magnetic field intensity of pancratic lens front focal plane and magnetic field gradient before and after the magnet of described rear end.
Preferably, said apparatus has following characteristics:
Described device also can comprise microscope, and described magnetic object lens are installed on the described microscope, and described microscope links to each other with charge coupled device with described lighting source respectively.
In order to address the above problem, the invention provides the integrated system of a kind of imaging magnetic tweezers and single molecular fluorescence technology, comprise aforesaid imaging magnetic tweezers, the central processing system that links to each other with described CCD, single molecular fluorescence imaging device and sample, described imaging magnetic tweezers and single molecular fluorescence imaging device are staggered relatively, are positioned at the both sides of sample.
In order to address the above problem, the invention provides a kind of magnetic object lens, comprise object lens and the magnetic field gradient and the adjustable ring-shaped magnet of intensity that are integrated in the object lens head, the described ring-shaped magnet that is integrated in the object lens head is the magnetic tweezer, comprise two blocks of ring-shaped magnets, be respectively front end magnet and rear end magnet, described front end magnet is as the emergent pupil of described object lens; Described rear end magnet is enclosed within the object lens periphery, and its magnetic field and the stack of front end magnet are by sliding the magnetic field intensity of pancratic lens front focal plane and magnetic field gradient before and after the magnet of described rear end.
In order to address the above problem, the invention provides a kind of integrated method of aforesaid imaging magnetic tweezers and single molecular fluorescence technology that adopts, comprising:
Connect by the unimolecule that in sample cell, carries out " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured ", and it is imaging magnetic tweezers and single molecular fluorescence imaging device is staggered relatively, be positioned at the both sides of sample, unite use behind the aligning, handle and measurement to realize magnetic tweezer and the unimolecule mechanics of the integrated and inferior nano-precision of single molecular fluorescence technology.
Preferably, said method has following characteristics:
The unimolecule connection of described " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured " refers to: an end that connects handle is connected with super paramagnetic microsphere, the other end is connected with fluorescent microsphere, fluorescent microsphere is connected with the end of biomacromolecule to be measured, and the other end of biomacromolecule to be measured is connected with glass surface.
Preferably, said method has following characteristics:
Described imaging magnetic tweezers and single molecular fluorescence imaging device are united to use comprise: the magnetic object lens of described imaging magnetic tweezers carry out the unimolecule mechanics to sample and handle; Described single molecular fluorescence imaging device carries out the observation of fluorescence signal to biomolecule.
Preferably, said method has following characteristics:
Described connection handle is that DNA or polypeptide etc. can be done the biochemical biomolecule that connects.
The invention has the beneficial effects as follows:
1, can study biologic single molecular, comprise the folding and assembling of protein and nucleic acid interaction, biomacromolecule, the dynamics of biomolecule motor etc.;
2, integrated imaging magnetic tweezers and single molecular fluorescence technology, can measure the metamorphosis of the inferior nano-precision of biomacromolecule under controlled external force is handled, perhaps because the metamorphosis that the combination/assembling of other biological molecule causes, perhaps molecular motor moving and the change of configuration of the substrate that they cause along its track;
3, by the unimolecule interconnection technique of " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured ", realize that the unimolecule mechanics of inferior nano-precision is handled.
Description of drawings
Fig. 1 is magnetic field gradient and the adjustable magnetic object lens synoptic diagram of intensity of the embodiment of the invention;
Fig. 2 is the imaging magnetic tweezers synoptic diagram of the embodiment of the invention;
Fig. 3 is the microscopical imaging magnetic tweezers of the use of the embodiment of the invention synoptic diagram that links to each other with central processing system;
Fig. 4 is the integrated system schematic of the imaging magnetic tweezers of the embodiment of the invention and single molecular fluorescence technology;
Fig. 5 is the unimolecule connection diagram of the embodiment of the invention " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured ";
Fig. 6 is the Lambda DNA(DNA (deoxyribonucleic acid) that records with the imaging magnetic tweezers of application example of the present invention) stress strain curve.
Embodiment
Hereinafter will be elaborated to embodiments of the invention by reference to the accompanying drawings.Need to prove that under the situation of not conflicting, the embodiment among the application and the feature among the embodiment be combination in any mutually.
Propose among the present invention, adopt the imaging magnetic tweezers to solve the limitation of traditional magnetic tweezer manipulation technology, this imaging magnetic tweezers integrates magnetic tweezer and object lens, make a side of sample be used for doing unimolecule magnetic tweezer and measure that the opposite side of sample can be used for integrated single molecular fluorescence device and measure (single molecular fluorescence device itself also comprises a high power objective).And, the unimolecule interconnection technique that the present invention proposes a kind of " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured ", realized the combination of single molecule manipulation and single molecular fluorescence technology, not only overcome the defective on the magnetic tweezer manipulation technology principle, can realize that also the unimolecule magnetic tweezer of inferior nano-precision is handled measurement.
Shown in Figure 1, the magnetic object lens 1 that magnetic field gradient and intensity are adjustable comprise that object lens 2 are integrated in magnetic field gradient and the adjustable ring-shaped magnet of intensity of object lens head.The ring-shaped magnet that wherein is integrated in the object lens head is the magnetic tweezer, comprises two blocks of ring-shaped magnets, is respectively front end magnet 3 and rear end magnet 4.The eyeglass of object lens 2 inside is arranged the eyeglass of pressing high-NA objective inside and is arranged, and meets the imaging requirements of high-NA objective, a little less than front end magnet 3 magnetic, is positioned at object lens 2 camera lenses foremost, both as the emergent pupil of object lens, is used as the part of magnetic tweezer again; Magnet 4 magnetic in rear end are strong, be enclosed within the periphery of object lens 2, be put in after the front end magnet 3, can be within the specific limits seesaw along the optical axis direction of object lens 2, the magnetic field superposition that the magnetic field that rear end magnet 4 produces and front end magnetic tweezer 3 produce is by the magnetic field intensity and the magnetic field gradient that move forward and backward to regulate object lens 2 front focal planes of rear end magnet 4.
As shown in Figure 2, imaging magnetic tweezers 5 for the embodiment of the invention, this imaging magnetic tweezers 5 comprises above-mentioned magnetic object lens 1, lighting source 6 and charge coupled device (CCD) 7, magnetic object lens 1 and lighting source 6 and charge coupled device (CCD) 7 combinations carry out the unimolecule mechanics when realizing the super paramagnetic microsphere imaging and handle.Wherein, lighting source 6 provides illumination for magnetic object lens 1, and charge coupled device (CCD) 7 is used for and will be converted into digital signal by the optical image that magnetic object lens 1 obtain.Magnetic object lens 1, lighting source 6 and charge coupled device (CCD) 7 can be fixed on carries out the experiment of magnetic tweezer on the optical table.
As shown in Figure 3, imaging magnetic tweezers 5 can include microscope, and links to each other with central processing system.Magnetic object lens 1 are installed on the microscope 8, lighting source 6 is connected with microscope by the interface of microscope 8, realize that 6 pairs of samples 9 of lighting source throw light on, charge coupled device (CCD) 7 is connected with the interface of microscope 8 equally, and be connected with central processing system 10, thereby the main frame 12 that the image information that sample 9 produces in charge coupled device (CCD) 7 is delivered to central processing system 10 is handled, the positional information of analytical calculation super paramagnetic microsphere, and then the conformation change of the reckoning biomacromolecule that super paramagnetic microsphere connected, and in display 11 demonstrations, realized that like this imaging magnetic tweezers uses at simple microscope, carried out the experiment of magnetic tweezer.
As shown in Figure 4, be that the glimmering device of imaging magnetic tweezers and unimolecule is integrated.Connect by the unimolecule that in sample cell, carries out " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured ", and it is imaging magnetic tweezers 5 and single molecular fluorescence imaging device 13 is staggered relatively, be positioned at the both sides of sample 9, unite use behind the aligning, handle and measurement to realize magnetic tweezer and the unimolecule mechanics of the integrated and inferior nano-precision of single molecular fluorescence technology.Adjustable magnetic object lens 1 in the imaging magnetic tweezers 5 must be regulated coaxial with the viewing objective (not drawing among the figure) in the single molecular fluorescence device 13, make imaging magnetic tweezers 5 and single molecular fluorescence device 13 observed be same area, 5 pairs of samples of imaging magnetic tweezers 9 carry out the unimolecule mechanics and handle, the image information that obtains passes to the main frame 12 of central processing system 10 and handles, draw the mechanical information of super paramagnetic microsphere, and in display 11 demonstrations, 13 pairs of samples of single molecular fluorescence device 9 carry out the single molecular fluorescence acquisition of signal, the fluorescence signal that obtains is handled by the disposal system that single molecular fluorescence device 13 carries, draw corresponding single molecular fluorescence information, wherein single molecular fluorescence device 13 comprises a variety of, as total reflection fluorescence microscopy device, the perhaps molecular motor sniffer of walking at DNA, also can be FRET(fluorescence resonance energy transfer, FRET (fluorescence resonance energy transfer)) experimental provision etc. is so long as the experimental provision of single molecular fluorescence just can be undertaken integrated by said method and imaging magnetic tweezers 5.
As shown in Figure 5, the unimolecule that is " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured " connects, comprise super paramagnetic microsphere 14, connect handle 15, fluorescent microsphere 16, biomacromolecule 17 to be measured, glass surface 18, an end that connects handle 15 is connected with super paramagnetic microsphere 14, the other end is connected with fluorescent microsphere 16, fluorescent microsphere 16 is connected with the end of biomacromolecule 17 to be measured again, the other end of biomacromolecule 17 to be measured is connected with glass surface 18, super paramagnetic microsphere 14 is handled and control by imaging magnetic tweezer 4, the fluorescence intensity of fluorescent microsphere 16 is surveyed by single molecular fluorescence device 13, when adopting the coupling of total reflection fluorescent apparatus and imaging magnetic tweezers, can change the variable in distance of extrapolating fluorescent microsphere 16 and glass surface by the light intensity of fluorescent microsphere, realize the manipulation of unimolecule mechanics and the measurement of inferior nano-precision, provide the method for imaging magnetic tweezer measurement magnetic force below, also provided the method for calculating the variation of distance between fluorescent microsphere and the glass surface by the variation of fluorescent microsphere fluorescence intensity.
As shown in Figure 6, be the Lambda DNA stress strain curve that records with the imaging magnetic tweezers of application example of the present invention.
In the experiment of magnetic tweezer, the stressed size of super paramagnetic microsphere is determined by the distance between the magnetic field gradient around the super paramagnetic microsphere and super paramagnetic microsphere and the magnetic tweezer.Super paramagnetic microsphere is stressed to be provided by following formula:
In the formula, m is magnetic moment, and B is magnetic field intensity, and X is the direction vector of magnetic field gradient.
But carry out relatively difficulty of force measurement with said method, in general, unimolecule is provided by the Brownian movement of super paramagnetic microsphere by force measurement, and is as follows:
In the formula, k
BBe Boltzmann constant,
T is absolute temperature,
＜z〉be monomolecular average length,
＜(δ x)
2It is the variance of super paramagnetic microsphere x direction.
When adopting the coupling of total reflection fluorescent apparatus and imaging magnetic tweezers to carry out the fluorescence signal detection, light intensity variation and the variable in distance relation of fluorescent microsphere is provided by following formula:
Wherein,
In the formula, λ is the wavelength of incident laser,
n
1Total reflection is the optically denser medium refractive index at the interface,
n
2Be the optically thinner medium refractive index,
θ is total reflection light beam incident angle,
Z is the distance between fluorescent microsphere and the glass surface,
The fluorescent microsphere light intensity of I (z) when being distance z.
In the experimental provision of above-mentioned total reflection fluorescent apparatus and the coupling of imaging magnetic tweezers, can directly measure the suffered magnetic force of super paramagnetic microsphere by the image information that detects in the imaging magnetic tweezers, handle thereby carry out the unimolecule mechanics; Measure the fluorescence intensity information that fluorescent microsphere produces by the total reflection fluorescent apparatus, and then calculate the variation of relative distance between fluorescent microsphere and the glass surface, thereby obtain high-resolution biomacromolecule conformation change information.
Imaging magnetic tweezers of the present invention can carry out the magnetic tweezer on the one hand and handle experiment, can also with the integrated application of multiple single molecular fluorescence technology, when adopting the coupling of total reflection fluorescent apparatus and imaging magnetic tweezer to carry out the fluorescence signal detection, utilize unimolecule interconnection technique of the present invention, integrated imaging magnetic tweezers and single molecular fluorescence technology, can either carry out fluorescence signal to sample and survey, also can carry out mechanics to sample and handle, and fluorescence signal and mechanics are handled separate, do not disturb mutually; On the other hand, the imaging magnetic tweezers can apply the constraint of power to the super paramagnetic microsphere in the sample, reduce Blang's fluctuation of this unimolecule connected system effectively, make integrated single molecular fluorescence device obtain stable fluorescence signal more, overcome in the common magnetic tweezers the big defective of fluctuation that is caused by Brownian movement when magnetic microsphere positioned, improved the experimental precision when single molecule manipulation is measured.
The above is the preferred embodiments of the present invention only, is not limited to the present invention, and for a person skilled in the art, the present invention can have various changes and variation.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (8)
1. imaging magnetic tweezers, comprise lighting source and charge coupled device (CCD), it is characterized in that, also comprise the magnetic object lens that magnetic field gradient and magnetic field intensity are adjustable, described magnetic object lens comprise object lens and are integrated in magnetic field gradient and the adjustable ring-shaped magnet of intensity of object lens head that described ring-shaped magnet is the magnetic tweezer; The described ring-shaped magnet that is integrated in the object lens head comprises two blocks of ring-shaped magnets, is respectively front end magnet and rear end magnet, and described front end magnet is as the emergent pupil of described object lens; Described rear end magnet is enclosed within the object lens periphery, by sliding before and after the magnet of described rear end, regulates magnetic field intensity and the magnetic field gradient of object lens front focal plane; Described magnetic object lens and lighting source and CCD combination is carried out the unimolecule mechanics when realizing the super paramagnetic microsphere imaging and is handled.
2. device as claimed in claim 1 is characterized in that, described device also comprises microscope, and described magnetic object lens are installed on the described microscope, and described microscope links to each other with charge coupled device with described lighting source respectively.
3. the integrated system of an imaging magnetic tweezers and single molecular fluorescence technology, it is characterized in that, comprise imaging magnetic tweezers as claimed in claim 1, the central processing system that links to each other with described CCD, single molecular fluorescence imaging device and sample, described imaging magnetic tweezers and single molecular fluorescence imaging device are staggered relatively, are positioned at the both sides of sample.
4. magnetic object lens, it is characterized in that, comprise object lens and the magnetic field gradient and the adjustable ring-shaped magnet of intensity that are integrated in the object lens head, the described ring-shaped magnet that is integrated in the object lens head is the magnetic tweezer, comprise two blocks of ring-shaped magnets, be respectively front end magnet and rear end magnet, described front end magnet is as the emergent pupil of described object lens; Described rear end magnet is enclosed within the object lens periphery, and its magnetic field and the stack of front end magnet are by sliding the magnetic field intensity of pancratic lens front focal plane and magnetic field gradient before and after the magnet of described rear end.
5. one kind is adopted the integrated method of imaging magnetic tweezers as claimed in claim 1 and single molecular fluorescence technology, comprising:
Connect by the unimolecule that in sample cell, carries out " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured ", and it is imaging magnetic tweezers and single molecular fluorescence imaging device is staggered relatively, be positioned at the both sides of sample, unite use behind the aligning, handle and measurement to realize magnetic tweezer and the unimolecule mechanics of the integrated and inferior nano-precision of single molecular fluorescence technology.
6. method as claimed in claim 5 is characterized in that,
The unimolecule connection of described " super paramagnetic microsphere-connection handle-fluorescent microsphere-biomacromolecule-glass surface to be measured " refers to: an end that connects handle is connected with super paramagnetic microsphere, the other end is connected with fluorescent microsphere, fluorescent microsphere is connected with the end of biomacromolecule to be measured, and the other end of biomacromolecule to be measured is connected with glass surface.
7. method as claimed in claim 5 is characterized in that,
Described imaging magnetic tweezers and single molecular fluorescence imaging device are united to use comprise: the magnetic object lens of described imaging magnetic tweezers carry out the unimolecule mechanics to sample and handle; Described single molecular fluorescence imaging device carries out the observation of fluorescence signal to biomolecule.
8. method as claimed in claim 6 is characterized in that,
Described connection handle is that DNA or polypeptide etc. can be done the biochemical biomolecule that connects.
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| CN105004702A (en) * | 2015-06-18 | 2015-10-28 | 华中科技大学 | Dual-imaging magnetic tweezer system |
| CN106568714B (en) * | 2015-10-13 | 2019-04-05 | 中国科学院物理研究所 | Biologic single molecular manipulation detection system and corresponding capillary based on transverse magnetic tweezer |
| CN108324293B (en) * | 2018-01-17 | 2019-12-24 | 北京航空航天大学 | Skeletal muscle myotube mechanics determination chip and preparation method thereof |
| RU2746359C1 (en) * | 2019-11-29 | 2021-04-12 | Алексей Андреевич Никитин | Method for determining the energy of individual magnetic particles acquired by them in a low-frequency alternating magnetic field |
| CN111721504B (en) * | 2020-06-17 | 2022-02-18 | 中国科学院物理研究所 | Method for measuring and calculating height conversion coefficient of magnetic tweezers under low force and application |
| CN112255396A (en) * | 2020-10-15 | 2021-01-22 | 南开大学 | Single-molecule mechanical method for measuring small-molecule drug inhibition protein nucleic acid interaction |
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