CN111103441B - Force clamp experiment method of biomembrane mechanical probe system with feedback control function - Google Patents
Force clamp experiment method of biomembrane mechanical probe system with feedback control function Download PDFInfo
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- CN111103441B CN111103441B CN201911268346.9A CN201911268346A CN111103441B CN 111103441 B CN111103441 B CN 111103441B CN 201911268346 A CN201911268346 A CN 201911268346A CN 111103441 B CN111103441 B CN 111103441B
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Abstract
The invention discloses a biomembrane mechanical probe system force clamp experimental method with a feedback control function. In the force clamp experiment, a high-speed camera monitors the boundary position of a probe ball in real time, a piezoelectric motion platform implements feedback compensation according to the deviation between the boundary position of the probe ball corresponding to a preset force value and the boundary position of the real-time probe ball, the boundary position of the real-time probe ball is input into a filter of a PID control module, and a PID controller controls a motion module of the piezoelectric motion platform by combining with the deviation value of the boundary position of the probe ball to execute feedback compensation motion; and the data recording time interval is dynamically adjusted according to the length of the recording binding time in the experiment. The invention obviously improves the stability of the force acting on the molecular bond, can apply stable acting force to the molecular bond with slower dissociation rate, obviously prolongs the recording time limit of the binding time of the molecular bond, and can stably record the binding time of the single molecular bond for a long time.
Description
Technical Field
The invention relates to a quantitative detection method for detecting the dissociation rate of interaction between biological macromolecules, in particular to a super-alignment force clamp experimental method based on a biological membrane mechanics probe system.
Background
With the development of the monomolecular force spectrum technology, the regulation and control rules of various biological materials on monomolecular bonds have been analyzed by the techniques such as an atomic force microscope, optical tweezers, magnetic tweezers, a biomembrane mechanical probe and the like at the monomolecular level. The biomembrane mechanical probe (BFP) system has the advantages of small elastic coefficient, low operation difficulty, easy operation on living cells and the like, and is particularly suitable for in-situ detection of interaction of biomacromolecules on the surfaces of the living cells. As an important component of a dynamic force spectrum experiment, the 'force clamp' experiment quickly loads acting force acting on a molecular bond to a set value, observes and collects the binding time of a single molecular bond under the action of the set force value, thereby directly obtaining the stress regulation rule of the molecular bond without model fitting, and obtaining the dissociation rate (k) of the molecular bond under the '0' force condition according to 'bell' model fittingoff). Therefore, the 'force clamp' experiment based on the biological membrane mechanical probe system is particularly suitable for in-situ detection of the dissociation rate of the molecular bond related to the membrane protein.
Although the "force clamp" experiment based on the biomembrane mechanical probe system has detected various transient intermolecular interactions with fast dissociation rates, it cannot be applied to the research of intermolecular interactions with slow dissociation rates. This is because, due to the lack of force feedback control during the detection process, various disturbances will cause the recorded force values to continuously shift during the long binding time of the molecular bonds, eventually resulting in large deviations of the measurement results.
Therefore, solving the deviation of recorded force values is the first condition to apply the 'force clamp' technology based on the biomembrane mechanical probe system to accurately detect the dissociation rate of the strong intermolecular interaction.
Disclosure of Invention
In order to solve the problems in the background art, the invention aims to provide a force clamp technology based on a biomembrane mechanical probe system with a feedback control function. By embedding a PID feedback control algorithm in the stage of recording the molecular bond combination time in the experimental control program of the force clamp, the force value recorded in the stage of recording the molecular bond combination time is stably clamped at a set position, namely the force acting on the molecular bond is stably clamped.
In order to achieve the purpose, the invention adopts the technical scheme that:
the force clamp experiment relates to a probe end and a target end, wherein the probe end comprises a probe ball and red blood cells, and the method comprises the following steps:
1) an initialization stage:
the piezoelectric motion platform controls the target end to be far away from the probe end to be in an initial position and to be static, the red blood cells are in an initial state at the moment, the probe small ball is positioned at the side boundary close to the red blood cells and serves as a reference mark position, the reference mark position is tracked in real time through high-speed addition shooting and serves as an initial reference mark position, the average value of the reference mark positions recorded within 0.2 second serves as the initial reference mark position, and then the next stage is started;
2) and (3) an impact stage: monitoring the position of the reference mark in real time, driving the cells/globules at the target end to move close to the red blood cells by the piezoelectric motion platform through the second micropipette at a preset speed, pushing the probe globules to compress the red blood cells in a centering manner until the position of the reference mark moves by a preset compression distance, and entering the next stage;
3) and (3) a contact stage: monitoring the position of the reference mark in real time, keeping the piezoelectric motion platform static, enabling the probe ball to be in stable contact with the cell/ball, and entering the next stage after preset contact time;
4) and (3) withdrawal stage: the piezoelectric motion platform drives the cells/small balls at the target end to withdraw and move away from the red blood cells at a preset speed through the second micropipette; in the withdrawal process, monitoring the position of the reference marker, if the position of the reference marker moves by a length corresponding to a preset force value compared with the position of the initial reference marker, and the force value is a force value acting on a molecular bond, namely the red blood cell is stretched by a set length, the experiment is an adhesion event, the piezoelectric motion platform immediately stops the current withdrawal motion, and a binding time recording stage is entered; if the reference mark position is restored to the initial reference mark position and is not stretched, directly entering 6) a resetting stage;
5) and (3) combining a time recording stage: and monitoring the position of the reference mark in real time, taking the position of the reference mark monitored in real time as the position of the actual reference mark, and implementing feedback compensation by the piezoelectric motion platform according to the deviation between the position of the reference mark corresponding to the preset force value and the position of the actual reference mark: filtering the actual reference mark position by a filter of a PID controller, subtracting the actual reference mark position from a reference mark position corresponding to a preset force value to obtain a deviation, inputting the deviation into the PID controller, inputting a deviation control quantity output by the PID controller into a motion module for controlling a piezoelectric motion platform, executing feedback compensation motion until the reference mark position is restored to the initial reference mark position again, namely the molecular bond is broken, the red blood cell is restored to a natural '0' force state, and entering a resetting stage;
6) a reset phase: and monitoring the position of the reference mark in real time, withdrawing the piezoelectric motion platform to the initial position, ending the current cycle, and preparing the next cycle by measuring force value data and storing data.
In the biomembrane mechanical probe system, the action of red blood cells is a force sensor, the red blood cells are similar to a linear spring in a certain force range, and the change of the position of a reference mark can be converted into a force value acting on a molecular bond in real time according to the elastic coefficient of the red blood cells.
The invention adds a reference small ball in a force clamp experiment, utilizes the strong interaction between protein molecules to stick to the tip of a micro-pipette sucking red blood cells, and accurately tracks the force acting on a molecular bond in a double-boundary tracking mode.
The PID controller adopts pure proportional feedback control, and the proportional parameter is 1.
The method adopts the following biomembrane mechanical probe system, and the specific implementation biomembrane mechanical probe system comprises a probe end and a target end, wherein the probe end comprises a first micropipette, red blood cells and a probe bead, and the target end comprises cells/beads and a second micropipette; the end part of the first micropipette sucks red blood cells, the probe beads are connected to the red blood cells through intermolecular interaction (such as the interaction between streptavidin and biotin), and a target protein molecule is coated on the surface of the probe beads; the end of the second micropipette aspirates cells/globules, which express/surface coat another target protein molecule, the probe globules are connected/located between the red blood cells and the cells/globules; the second micro-pipette sucks the cells/beads and is connected to the piezoelectric motion platform, and the piezoelectric motion platform drives the second micro-pipette to move so as to drive the cells/beads 4 to be far away from or close to the probe beads at the probe end to carry out the force clamp experiment.
The small probe ball is a glass ball with the diameter of about 2 microns and is made of borosilicate.
In the force clamp experiment, 2 times of the initial data sampling time interval is used as a data recording time interval to sample the force value data and record the force value data in a register, and when the molecular bond binding time exceeds 5 seconds, the data recording time interval is increased to 25 times of the sampling time interval; when the number of times of recording data exceeds 5000 times, the data recording time interval is further increased by 5 times.
The invention has the beneficial effects that:
the feedback control program of the embedding force in the stage of recording the molecular bond binding time corresponding to the control program of the original biomembrane mechanical probe system realizes the stable 'clamping' of the recording force in the molecular bond binding time in the 'force clamp' experiment, and greatly prolongs the recording time limit of the molecular bond binding time through the recording time interval of dynamic adjustment.
The invention mainly aims at the research technology of the regulation and control rule of the dissociation rate under the action of stronger intermolecular interaction in the field of life science, and can more accurately and effectively research the change rule of the binding time of the single molecular bond under the action of biological force. Compared with the original 'force clamp' experiment, the 'force clamp' experiment related by the invention has the following advantages:
1) recording the stable clamping of the force value in the combination time to the set force value;
2) the recording time limit of the molecular bond binding time is prolonged to more than 200 seconds.
Therefore, the method can apply stable acting force to the molecular bond with the slow dissociation rate, record the binding time of the molecular bond for a long time, and is particularly suitable for in-situ detection of the dissociation rate stress regulation rule of the strong intermolecular interaction.
Drawings
FIG. 1 is a schematic diagram of a biomembrane based mechanical probe system according to the present invention.
Fig. 2 is a schematic diagram of feedback control according to the present invention.
Fig. 3 is a diagram of an example result of dynamically adjusting data recording time in accordance with the present invention.
Fig. 4 is an example of data recorded from a raw biomembrane mechanical probe experiment.
In the figure: 1. the method comprises the following steps of firstly, preparing a first micropipette, 2, red blood cells, 3, a probe ball, 4, cells/balls, 5, secondly, preparing a micropipette, 6, a piezoelectric motion platform, 7, a boundary, 8, and a force clamp technology force-time data example with a feedback control function, and 9, and a force clamp technology recording time interval recording time data example with a feedback control function.
Detailed Description
The invention is further illustrated by the following figures and examples.
The method adopts the following biological membrane mechanical probe system, as shown in fig. 1, the specific biological membrane mechanical probe system comprises a probe end and a target end, wherein the probe end comprises a first micropipette 1, red blood cells 2 and a probe pellet 3, and the target end comprises a cell/pellet 4 and a second micropipette 5; (ii) a Sucking red blood cells 2 from the end of a first micropipette 1, connecting a probe bead 3 to the front end of the red blood cells 2 through strong intermolecular interaction (such as interaction between streptavidin and biotin), and coating a target protein molecule on the surface of the probe bead 3; sucking the cells/globules 4 from the end of the second micropipette 5, wherein the cells/globules (4) express/are coated with another target protein molecule, if the cells/globules are the cells 4, the cells/globules express another target protein molecule, and if the cells/globules are the globules 4, the cells/globules are coated with another target protein molecule; (ii) a The second micro-pipette 5 sucks the cell/pellet 4 and is connected to the piezoelectric motion platform 6, and the piezoelectric motion platform 6 drives the second micro-pipette 5 to move so as to drive the cell/pellet 4 to be far away from or close to the probe pellet 3 at the probe end to perform a force clamp experiment.
The probe end is formed by a first micropipette 1, red blood cells 2 and a probe ball 3 and is kept fixed; the cell/pellet 4 and the second micropipette 5 form a target end, the force acting on the molecular bond is easily disturbed due to the deformation of cell membranes, environmental disturbance and the like (as shown in figure 4), and the piezoelectric motion platform 6 drives and controls the target end to move.
In a specific implementation, the probe bead 3 has a diameter of about 2 microns.
The specific embodiment and the implementation process of the invention comprise the following steps:
1) an initialization stage:
the piezoelectric motion platform 6 controls the target ends 4 and 5 to be far away from the probe ends 1, 2 and 3 to be at initial positions and to be static, at the moment, the red blood cell 2 is in an initial state, the probe small ball 3 is positioned at a side boundary 7 close to the red blood cell 2 to serve as a reference mark position, the reference mark position is tracked in real time through high-speed addition shooting to serve as an initial reference mark position, the average value of the reference mark positions recorded within 0.2 second is taken as an initial reference mark position, and then the next stage is started; (ii) a
2) And (3) an impact stage: monitoring the position of a reference mark in real time, driving the cells/globules 4 at the target end to move towards the direction close to the red blood cells 2 by the piezoelectric motion platform 6 through the second micropipette 5 at a preset speed, pushing the probe globules 3 to the center and compressing the red blood cells 2 until the position of the reference mark moves by a preset compression distance, and entering the next stage;
3) and (3) a contact stage: monitoring the position of the reference mark in real time, keeping the piezoelectric motion platform 6 static, stably contacting the probe bead 3 with the cell/bead 4, and entering the next stage after preset contact time;
4) and (3) withdrawal stage: the piezoelectric motion platform 6 drives the cells/globules 4 at the target end to withdraw and move towards the direction far away from the red blood cells 2 according to the preset speed through the second micropipette 5;
in the withdrawal process, monitoring the position of the reference marker, if the position of the reference marker moves by a length corresponding to a preset force value compared with the position of the initial reference marker, and the force value is a force value acting on a single molecular key, namely the red blood cell 2 is stretched by a set length, the experiment is an adhesion event, the piezoelectric motion platform 6 immediately stops the current withdrawal motion, and the next stage is a combined time recording stage;
if the reference mark position is only restored to the original reference mark position and is not stretched, directly entering 6) a resetting stage;
5) and (3) combining a time recording stage: monitoring the position of the reference mark in real time, and meanwhile, as shown in fig. 2, taking the position of the reference mark monitored in real time as the position of the actual reference mark, and implementing feedback compensation by the piezoelectric motion platform 6 according to the deviation between the position of the reference mark corresponding to the preset force value and the position of the actual reference mark: after the actual reference mark position is filtered by a filter of a PID controller, the actual reference mark position is subtracted from a reference mark position corresponding to a preset force value to obtain deviation, the deviation is input into the PID controller, deviation control quantity output by the PID controller is input into a motion module for controlling the piezoelectric motion platform 6, feedback compensation motion is executed until the reference mark position is restored to the initial reference mark position again, namely, a molecular bond is automatically broken, and a resetting stage is started.
The PID controller adopts pure proportional feedback control, and the proportional parameter is 1.
Thus, the present invention stably maintains the force acting on the molecular bond at the set force value by performing the feedback compensation motion by the piezoelectric motion stage 6(Physik Instrument P-753.1CD) of the target end according to the actual reference mark position and the preset reference mark position. The preset reference mark position is the initial reference mark position plus the red blood cell deformation corresponding to the preset force value.
6) A reset phase: and monitoring the position of the reference mark in real time, withdrawing the piezoelectric motion platform 6 to the initial position, ending the current cycle, and preparing the next cycle by measuring the force value data and storing the data.
In the force clamp experiment, 2 times of the initial data sampling time interval is used as the data recording time interval to sample the force value data and record the force value data in the register, and when the molecular bond binding time exceeds 5 seconds, the data recording time interval is increased to 25 times of the sampling time interval; when the number of times of recording data exceeds 5000 times, the data recording time interval is further increased by 5 times, so that the molecular bond binding time of more than 200 seconds can be stably recorded.
The invention dynamically increases the time interval of data recording according to the length of the recorded combination time on the basis of ensuring the highest sampling frequency to be 1.2kHz, thereby avoiding the overflow of a computer memory caused by overlarge recorded data and solving the technical problems that the register capacity of the computer memory is limited and long-time experimental data cannot be effectively stored in the experimental process of the biomembrane mechanical probe system.
Data from experiments recording long binding times (about 90s) results are shown in figure 3, for "force-time" data example 8 and "recording time interval-recording time" data example 9 under the action of a stabilizing force clamp. The same experiment was carried out with the original biomembrane mechanical probe system without the feedback control function, and only 15 seconds of data results were stored after several times of execution, and the data results are shown in fig. 4.
The comparison shows that the measured result is very stable, and the data with longer binding time can be stored under the condition of the same register capacity, which reflects that the invention can stably clamp the position of the boundary 7 of the probe bead 3, and overcomes the problems of disturbance of force acting on a single molecular bond, limited recording time length of the binding time of the molecular bond and the like caused by factors such as environmental disturbance, cell membrane deformation and the like.
The foregoing detailed description is intended to illustrate and not limit the invention, which is intended to be within the spirit and scope of the appended claims, and any changes and modifications that fall within the true spirit and scope of the invention are intended to be covered by the following claims.
Claims (5)
1. A biomembrane mechanical probe system force clamp experiment method with feedback control function, the force clamp experiment involves probe end and target end, the probe end includes the probe globule (3), red blood cell (2), characterized by that: the method comprises the following steps:
1) an initialization stage:
the piezoelectric motion platform (6) controls the target ends (4 and 5) to be far away from the probe ends (1, 2 and 3) to be at an initial position and to be static, at the moment, the red blood cells (2) are in an initial state, the probe small balls (3) are positioned at the side boundary (7) close to the red blood cells (2) to serve as reference mark positions, the reference mark positions are shot by a high-speed camera to be tracked in real time to serve as initial reference mark positions, the average value of the reference mark positions recorded within 0.2 second is used as the initial reference mark position, and then the next stage is started;
2) and (3) an impact stage: monitoring the position of a reference mark in real time, driving a cell/pellet (4) at a target end to move close to a red blood cell (2) by a piezoelectric motion platform (6) through a second micropipette (5) at a preset speed, pushing a probe pellet (3) to compress the red blood cell (2) in a centering manner until the position of the reference mark moves by a preset compression distance, and entering the next stage;
3) and (3) a contact stage: monitoring the position of a reference mark in real time, keeping the piezoelectric motion platform (6) static, stably contacting the probe small ball (3) with the cell/small ball (4), and entering the next stage after preset contact time;
4) and (3) withdrawal stage: the piezoelectric motion platform (6) drives the cells/small balls (4) at the target end to retreat and move away from the red blood cells (2) at a preset speed through the second micropipette (5); in the withdrawal process, monitoring the position of the reference marker, if the position of the reference marker moves by a length corresponding to a preset force value compared with the position of the initial reference marker, namely the red blood cell (2) is stretched by a set length, the experiment is an adhesion event, the piezoelectric motion platform (6) immediately stops the current withdrawal motion, and a binding time recording stage is entered; if the reference mark position is restored to the initial reference mark position and is not stretched, directly entering 6) a resetting stage;
5) and (3) combining a time recording stage: and monitoring the position of the reference mark in real time, and meanwhile, taking the position of the reference mark monitored in real time as the position of an actual reference mark, and implementing feedback compensation by the piezoelectric motion platform (6) according to the deviation between the position of the reference mark corresponding to a preset force value and the position of the actual reference mark: filtering the actual reference mark position by a filter of a PID controller, subtracting the actual reference mark position from a reference mark position corresponding to a preset force value to obtain a deviation, inputting the deviation into the PID controller, inputting a deviation control quantity output by the PID controller into a motion module of a control piezoelectric motion platform (6), executing feedback compensation motion until the reference mark position is restored to the initial reference mark position again, namely the molecular bond is broken, restoring the red blood cells to a natural '0' force state, and entering a resetting stage;
6) a reset phase: and (3) monitoring the position of the reference mark in real time, withdrawing the piezoelectric motion platform (6) to the initial position, finishing the current cycle, and preparing the next cycle by measuring the data of the force value and storing the data.
2. The method for testing the force clamp of the biomembrane mechanical probe system with the feedback control function as claimed in claim 1, wherein the method comprises the following steps: the PID controller adopts pure proportional feedback control, and the proportional parameter is 1.
3. The method for testing the force clamp of the biomembrane mechanical probe system with the feedback control function as claimed in claim 1, wherein the method comprises the following steps: the method adopts the following biological membrane mechanical probe system, the specific biological membrane mechanical probe system comprises a probe end and a target end, the probe end comprises a first micropipette (1), red blood cells (2) and a probe pellet (3), and the target end comprises cells/pellets (4) and a second micropipette (5); the end part of the first micropipette (1) sucks red blood cells (2), the probe beads (3) are connected to the red blood cells (2) through intermolecular interaction, and a target protein molecule is coated on the surfaces of the probe beads (3); sucking cells/beads (4) at the end of a second micropipette (5), wherein the cells/beads (4) express/are coated with another target protein molecule, and the probe beads (3) are connected/positioned between the red blood cells (2) and the cells/beads (4); the second micro-suction pipe (5) sucks the cells/small balls (4) and is connected to the piezoelectric motion platform (6), the piezoelectric motion platform (6) drives the second micro-suction pipe (5) to move so as to drive the cells/small balls (4) to be far away from or close to the probe small balls (3) at the probe end to carry out force clamp experiments.
4. The method for testing the force clamp of the biomembrane mechanical probe system with the feedback control function as claimed in claim 3, wherein the method comprises the following steps: the probe small ball (3) is a glass ball with the diameter of about 2 microns.
5. The method for testing the force clamp of the biomembrane mechanical probe system with the feedback control function as claimed in claim 1, wherein the method comprises the following steps: in the force clamp experiment, 2 times of the initial data sampling time interval is used as a data recording time interval to sample the force value data and record the force value data in a register, and when the molecular bond binding time exceeds 5 seconds, the data recording time interval is increased to 25 times of the sampling time interval; when the number of times of recording data exceeds 5000 times, the data recording time interval is further increased by 5 times.
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