CN111640466B - A modeling-based method for obtaining synthetic parameters of stable DNA tetrahedra - Google Patents
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Abstract
本发明公开了一种基于建模的稳定性DNA四面体合成参数的获取方法，对DNA四面体的分支数及DNA四面体每条边上的交叉数进行计数，利用数学链环图构建DNA四面体纳米笼全原子模型，利用Gromacs软件对DNA四面体纳米笼全原子模型进行处理，并对构建的模型进行完整性和稳定性检测，获得具有完整性与稳定性的DNA四面体的分支数、交叉数及核苷酸总数。本发明能够获取稳定性DNA四面体的合成参数，根据这些合成参数能够指导合成稳定性的DNA四面体。
The invention discloses a modeling-based method for obtaining synthetic parameters of stable DNA tetrahedron, which counts the number of branches of DNA tetrahedron and the number of crossings on each edge of DNA tetrahedron, and uses mathematical chain loop diagram to construct DNA tetrahedron Using Gromacs software to process the DNA tetrahedral nanocage all-atom model, and check the integrity and stability of the constructed model to obtain the branch number, The number of crossovers and the total number of nucleotides. The invention can obtain the synthesis parameters of the stable DNA tetrahedron, and can guide the synthesis of the stable DNA tetrahedron according to these synthesis parameters.
Description
Technical Field
The invention relates to a method for acquiring stable DNA tetrahedron synthesis parameters based on modeling.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
DNA, also known as deoxyribonucleic acid, is composed of two complementary single strands intertwined with each other and plays an important role in the growth and development of all known organisms and many viruses. The main function of DNA in organisms is to store information that conveys instructions for constructing intracellular compounds such as proteins and ribonucleic acids. Professor n.c. seeman, university of new york, in 1982, designed a nucleic acid adaptor that utilized a specific oligonucleotide sequence that would preferentially form a fixed junction based on maximization of watson-crick base pairing. The idea provides an idea for the construction of three-dimensional DNA polyhedrons and promotes the development of DNA nanotechnology to open up a new direction. In the past two decades, the development of DNA nanotechnology has led to the increasing number of self-assembled DNA complexes with specific functions, such as tetrahedrons, cubes, octahedrons, dodecahedrons, triangular prisms, etc., three-dimensional polyhedral structures being created. However, in experiments, synthesis of many DNA polyhedra is time consuming and laborious due to high cost, preparation and purification of samples, difficulties in product yield and product characterization, and the like. With the development of software technology, the DNA polyhedron can be more conveniently researched by means of a molecular dynamics simulation method, namely a DNA atom model is constructed from the atom level, and the defects are made up by analyzing kinetic parameters through atom trajectory.
Molecular Dynamics Simulation (Molecular Dynamics Simulation) is a set of Molecular Simulation method, which mainly simulates the motion behavior of molecules and atom systems in a solvent system by a computer for a period of time. Macromolecular organisms in life sciences, such as proteins, fats, and carbohydrates, have been studied in the past based on various instruments and experimental means. However, these experimental approaches are only used to study the behavior of these biomacromolecules in a macroscopic view, and it is still difficult to study their movement behavior in an atomic scale. Such as protein folding in a living body, is a specific physical process by which to obtain a functional three-dimensional structure on its own. However, only partial folding details are obtained by laboratory instruments and the whole folding process cannot be studied intuitively. However, the development of computer software has made up for the shortcomings of obtaining this physical process, allowing researchers to closely observe the behavior of these biomolecules.
In recent years, molecular dynamics calculation has become one of the main methods for scientific research, since 2009 a. desideri group carries out a complete kinetic trajectory on a DNA octahedron through molecular dynamics simulation for the first time, a method for DNA polyhedron simulation calculation is developed at a high speed, the structural composition of a polyhedron used for simulation is changed from single to complex, and the simulation time is also changed from the first ten nanoseconds to several hundred nanoseconds today. The inventor of the invention discovers that the current simulation calculation of the DNA polyhedron mainly uses two simulation software of Amber and NAMD, the modeling and calculation are only carried out from a single angle in the prior report, the explanation of a mathematical theory level is not available, the process from the initial model construction to the dynamics simulation has certain limitation and deficiency, the integrity and the stability of the DNA tetrahedron cannot be evaluated, and the space capacity of the DNA tetrahedron cannot be improved.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for obtaining the synthesis parameters of a stable DNA tetrahedron based on modeling, which can determine the stable structure of the DNA tetrahedron, thereby improving the space capacity of the DNA tetrahedron.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for obtaining stable DNA tetrahedron synthesis parameters based on modeling comprises the following steps:
obtaining the branch number of a DNA tetrahedron and the crossing number of each edge of the DNA tetrahedron; drawing a mathematical chain ring graph according to the branch number and the cross number; constructing a DNA tetrahedral nanocage full-atom model according to the mathematical chain graph to obtain the total number of nucleotides;
carrying out solvation treatment on the DNA tetrahedral nanocage full-atom model by using Gromacs software to form a cubic box solvent system, and adding ions into the cubic box solvent system to keep the cubic box solvent system electrically neutral;
carrying out energy minimization treatment on the electrically neutral cube box solvent system by using Gromacs software to obtain a minimized structure file;
carrying out NVT stage processing by using the minimized structure file as an input file by the Gromacs software to obtain an NVT structure file;
the Gromacs software carries out NPT stage processing by taking the NVT structure file as an input file to obtain an NPT structure file;
the Gromacs software takes the NPT structure file as an input file to carry out molecular dynamics simulation (MD) stage processing to obtain an MD track file;
processing the MD track file by a module in Gromacs to obtain a Root mean square deviation (Root mean square deviation) value of the nucleic acid molecule structure along with the time change;
acquiring the integrity and stability of the DNA tetrahedron according to the root-mean-square deviation value and the running time;
repeating the steps to obtain the branch number, the crossing number and the total number of the nucleotides of the DNA tetrahedron with integrity and stability.
The number of branches of the DNA tetrahedron and the number of intersections on each edge of the DNA tetrahedron influence the space capacity of the DNA tetrahedron, but the DNA tetrahedron with larger space capacity can not exist completely and stably, if the research is directly carried out by adopting a synthesis mode, the success is too high, the method provided by the invention can obtain the integrity and stability of different numbers of branches, intersections and the total number of nucleotides, and the DNA tetrahedron with different space capacities can be synthesized according to the numbers of branches, intersections and the total number of nucleotides.
The number of branches, the number of intersections and the total number of nucleotides of the DNA tetrahedron with integrity and stability are synthesis parameters of the DNA tetrahedron with stability.
The invention has the beneficial effects that:
(1) according to the method, the track file is analyzed by directly adopting a built-in program after analog calculation is carried out by using Gromacs, so that the complicated process that the track file can be analyzed only by converting the track file after calculation by adopting other software is reduced.
(2) The invention constructs a DNA tetrahedral cage model by designing a mathematical tetrahedral chain ring model and carries out molecular dynamics simulation.
(3) The model of the invention is easy to obtain, the chain ring design is not complicated, the simulation main body structure can be replaced, and not only aiming at the DNA tetrahedron, other types of DNA polyhedrons are constructed according to the mathematical chain ring diagram.
(4) The invention has lower cost, and the modeling program PolygenDNA, the simulation software and the visualization program can be freely obtained from an official website and provide an operation instruction.
(5) The equipment configuration requirement is lower, a small computer workstation or a common PC can be used, parallel computing can be used, and the utilization efficiency of a graphics card (GPU) can reach 70%.
(6) The invention is convenient for the DNA polyhedron with an internal cavity structure to be widely applied in the direction of biological material synthesis and drug loading.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a chain-link diagram L of a DNA tetrahedral nanocage according to an embodiment of the present invention, A representing embodiment 1, B representing embodiment 2, and C representing embodiment 3, wherein each side of the smallest tetrahedral chain-link in embodiment 1 comprises only 2 crossovers, and embodiment 3 is a largest chain-link, each side comprising 6 crossovers.
FIG. 2 is a DNA tetrahedral nanocage space-filling all-atom model constructed corresponding to the chain-loop diagram according to an embodiment of the present invention, wherein A represents embodiment 1, B represents embodiment 2, and C represents embodiment 3, the two helical edges of the tetrahedron are constructed using standard B-DNA, and the vertex connector is composed of 5 thymidine.
FIG. 3 is a graph of RMSD (mean square deviation from heel) versus time for DNA tetrahedral nanocages of an embodiment of the present invention, similarly in the three figures, line 1, line 2 and line 3 represent the full atom structure, DNA double helix strand and thymidine connector portion, respectively, A represents example 1, B represents example 2, and C represents example 3. The results illustrate that example 1 nanocages undergo relatively little change from the initial structure, with lower RMSD values for the three moieties. The RMSD curve values for lines 2, 3 are very close as the number of crossings increases in the other two examples 2 and 3, i.e. the double helix edge of DNA has a significant effect on the stability of the whole cage as the number of DNA twists increases, and it is also shown from the side that the DNA tetrahedron constructed by the method used in the present invention can maintain structural integrity.
FIG. 4 is a graph of RG (radius of gyration) versus time for a DNA tetrahedral nanocage according to an embodiment of the present invention, with line 1, line 2, and line 3 representing the full atom structure, DNA double helix strand, and thymidine connector portion, respectively, A representing embodiment 1, B representing embodiment 2, and C representing embodiment 3. From the comparison of the simulation results of the three examples, it can be seen that by increasing the number of double helix edge crossings of the tetrahedron, the RG value has smaller fluctuation, and the convolution radius value of the whole nanocage is obviously increased, wherein the RG average values of examples 1, 2 and 3 are respectively 3.0, 4.6 and 5.9nm, which can better illustrate that the volume of the tetrahedral nanocage constructed in examples 2 and 3 is larger than that of the cage in example 1.
FIG. 5 is a graph showing the Local RMSF (Local root mean square fluctuation) of the 6 double helical sides of a DNA nanocage according to an embodiment of the present invention, in which two curves represent nucleotides on two complementary strands, A represents example 1, B represents example 2, and C represents example 3.
FIG. 6 is a graph representing the Global RMSF (Global root mean square deviation) of 6 double helical edges of a DNA nanocage according to an embodiment of the present invention, in which two curves represent nucleotides on two complementary strands, A represents example 1, B represents example 2, and C represents example 3.
FIG. 7 is a cross-correlation diagram of a DNA tetrahedral nanocage according to an embodiment of the present invention, wherein a represents example 1, B represents example 2, and C represents example 3, and the results show that two complementary single-strand correlation intensity values are most distributed in example 3, and example 2 is the second and the weakest in example 1, among the constructed DNA tetrahedral cages.
The connector cluster cumulative frequency distribution results for the DNA tetrahedral cage of the present example show that each connector is represented by the first three major conformational clusters, where the cluster distribution of the 12 connectors of the tetrahedral cage was calculated separately, a represents example 1, B represents example 2, and C represents example 3, showing that the conformational changes in the linker region exhibit some different behavior as the number of DNA crossings increases. For the nanocage structure in example 1, the conformations were in the most frequently occurring cluster of three in each connector region, exceeding 50% of the simulation time. In contrast, for example 2 and example 3, most conformations expressed as the three most clusters were modeled for more than 65% and 80% of time, respectively, indicating that the conformational variability is linearly decreasing in relation to the number of DNA crossovers in the three nanocages, demonstrating that the number of DNA double helix strands crossovers can be used as an alternative method to modulate the conformational variability of the nanocages while keeping the linker length unchanged, based on the analysis results in fig. 3-7 above, demonstrating that the three DNA tetrahedral models contained in examples 1-3 are stable and have significantly increased internal spatial capacity.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
In view of the fact that the integrity and stability of a DNA tetrahedron cannot be evaluated in the prior art, and therefore the space capacity of the DNA tetrahedron cannot be improved, the invention provides a method for obtaining a stability DNA tetrahedron synthesis parameter based on modeling.
The invention provides a method for acquiring a stable DNA tetrahedron synthesis parameter based on modeling, which comprises the following steps:
obtaining the branch number of a DNA tetrahedron and the crossing number of each edge of the DNA tetrahedron; drawing a mathematical chain ring graph according to the branch number and the cross number; constructing a DNA tetrahedral nanocage full-atom model according to the mathematical chain graph to obtain the total number of nucleotides;
carrying out solvation treatment on the DNA tetrahedral nanocage full-atom model by using Gromacs software to form a cubic box solvent system, and adding ions into the cubic box solvent system to keep the cubic box solvent system electrically neutral;
carrying out energy minimization treatment on the electrically neutral cube box solvent system by using Gromacs software to obtain a minimized structure file;
carrying out NVT stage processing by using the minimized structure file as an input file by the Gromacs software to obtain an NVT structure file;
the Gromacs software carries out NPT stage processing by taking the NVT structure file as an input file to obtain an NPT structure file;
the Gromacs software takes the NPT structure file as an input file to carry out molecular dynamics simulation (MD) stage processing to obtain an MD track file;
processing the MD track file by a module in Gromacs to obtain a Root mean square deviation (Root mean square deviation) value of the nucleic acid molecule structure along with the time change;
acquiring the integrity and stability of the DNA tetrahedron according to the root-mean-square deviation value and the running time;
repeating the steps to obtain the branch number, the crossing number and the total number of the nucleotides of the DNA tetrahedron with integrity and stability.
The number of branches, the number of intersections and the total number of nucleotides of the DNA tetrahedron with integrity and stability are synthesis parameters of the DNA tetrahedron with stability.
The number of branches of the DNA tetrahedron and the number of intersections on each edge of the DNA tetrahedron influence the space capacity of the DNA tetrahedron, but the DNA tetrahedron with larger space capacity can not exist completely and stably, if the research is directly carried out by adopting a synthesis mode, the success is too high, the method provided by the invention can obtain the integrity and stability of different numbers of branches, intersections and the total number of nucleotides, and the DNA tetrahedron with different space capacities can be synthesized according to the numbers of branches, intersections and the total number of nucleotides.
In some embodiments of this embodiment, the mathematical link graph is rendered using CorelDRAW 12 software.
In some examples of this embodiment, the DNA tetrahedral nanocage full atom model was constructed using PolygenDNA model software.
In some examples of this embodiment, the solvation process employs an SPC/E solvent.
In some examples of this embodiment, sodium ions are added to the cube-box solvent system.
In some embodiments of this embodiment, the method of energy minimization is a steepest descent method.
In some embodiments of this embodiment, the total step size of the energy minimization process is 2000-6000 steps.
To avoid true phase boundaries, in some embodiments of this embodiment, a Periodic Boundary Condition (PBC) is used in the energy minimization process in X, Y and Z directions.
In order to avoid the influence of the nucleic acid structure in a fluctuating state in the simulation process, in some examples of this embodiment, the nucleic acid structure inside the cubic box solvent system in the energy minimization process is at a distance of 2 to 4 nanometers from the cubic box.
In some examples of this embodiment, the NVT stage process is performed using a V-reserve temperature control method.
In one or more embodiments, the reference temperature in the V-throttle temperature control method is 290-310K.
In some examples of this embodiment, 500 to 1500kJ mol are used in the NVT stage process-1*nm-2The constraining effect of (a) exerts a position-limiting force on all heavy atoms (Non-hydrogen atoms) in the nucleic acid structure.
In some embodiments of this embodiment, the NVT stage process uses the same force field, periodic boundary conditions, and electric field force calculation methods as the minimization process.
In some examples of this embodiment, the NVT stage processing is run for 1 nanosecond.
In some examples of this embodiment, the pressure and temperature are controlled separately during the NPT stage process using a Berendsen pressure control method and a V-temperature control method.
In one or more embodiments, the Berendsen pressure control method controls the pressure to be 0.9-1.1 bar, and the V-rescale temperature control method controls the temperature to be 290-310K.
In some examples of this embodiment, the NPT stage process uses the same force field, periodic boundary conditions, van der waals forces, and electric field force calculation methods as the energy minimization process.
In some embodiments of this embodiment, the location limits of the NPT stage processing are consistent with the location limits of the NVT stage processing.
In some examples of this embodiment, the positional constraint on the nucleic acid structure is removed during the NPT stage, and the force field, periodic boundary conditions, van der waals forces, and electrostatic forces are calculated during the molecular dynamics simulation stage in the same manner as the energy minimization process and the temperature control process is the same as the NVT stage process.
In some examples of this embodiment, the molecular dynamics simulation stage uses a Parriello-Rahman pressure control method to control pressure, a Particle Mesh Ewald (PME) method to document atomic electrostatic interactions, a LINCS algorithm to constrain all bonds, and a Lennard-Jones (L-J) potential to handle short range (Van der Waals) interactions.
In one or more embodiments, the Parriello-Rahman pressure control method controls the pressure to be 0.9-1.1 bar, the neighborhood search uses a Verlet neighborhood list scheme with buffering, and the update list frequency is set to be 9-11.
In some examples of this embodiment, the grid size spacing is set to 0.15 to 0.17nm during the molecular dynamics simulation phase.
In some examples of this embodiment, the truncation radii are set to 0.5 to 1.5nm in the molecular dynamics simulation stage.
In some examples of this embodiment, in the molecular dynamics simulation stage, a molecular dynamics simulation of 45-55 ns is performed on the system with a time step of 1-3 fs.
In some embodiments of this embodiment, before the module processing, the visualization software performs record analysis on the minimized track file, the NVT track file, the NPT track file, and the MD track file. It can be preliminarily determined whether the established DNA tetrahedron is stable.
In one or more embodiments, the visualization software is VMD-1.9.
In some examples of this embodiment, the analysis module in Gromacs performs conformational change analysis of nucleic acids in the MD track file, with a comparison of their spatial capacity or size being developed from two helical edges and two portions of the linker.
In some examples of this embodiment, the DNA tetrahedron is synthesized based on the number of branches, the number of intersections, and the total number of nucleotides of the DNA tetrahedron having integrity and stability.
In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the technical solution of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1:
(1) the mathematical chain graph 1TD of a particular topological property is plotted using coreldaw 12 software, as shown in fig. 1, with a chain graph containing 4 branches with a number of crossings on each side of 2.
(2) From the chain-link diagram, using PolygenDNA model software, set the vertex connector to consist of 5 thymidine, and by adjusting the module parameters in the program, a DNA tetrahedral nanocage all-atom model was constructed, as shown in fig. 2, named 1td.
Wherein: the number of double helix edge twists of the DNA tetrahedral cage model obtained by construction is respectively 1, the number of atoms of the full atomic model structure is 4586, the number of nucleotides forming the tetrahedral structure is 144, and the DNA tetrahedral full atomic structure is standard, corresponding to the number of intersections of the mathematical chain graph in the step (1).
(3) The nanocage structures were solvated using gromas 5.1.2 software, Charmm27 force field addition SPC/E solvent, forming a cubic box solvent system, adding cations (Na)+) The solvation system was kept electrically neutral and the resulting structure was named 1TD _ box _ ions.
Wherein: the number of water molecules contained in the above system was 118969, and the number of sodium ions was 140.
(4) The solvent system is treated with Energy minimization (Energy minimization) with total step size of 5000 steps by using a Steepest descnent (steeps defect), Periodic boundary conditions (Periodic boundary conditions) are used, namely pbc ═ xyz, Periodic boundaries are used in all directions to avoid real phase boundaries, the force field used is the same as that in step (3), atomic electrostatic interaction is calculated by using a Particle Mesh Ewald (PME) method, and short-range (van der waals) interaction is treated by using Lennard-Jones (L-J) potential, and the obtained structure file is sequentially named as: 1TD _ em.gro.
Wherein: the distance of the nucleic acid structure from the water box inside the solvent system was set to 2nm in consideration of the nucleic acid structure in a state of fluctuation during the simulation.
(5) Using 1000kJ mol-1*nm-2The position limiting force is applied to all heavy atoms (Non-hydrogen atoms) in the nucleic acid structure, the same force field, periodic boundary condition, van der waals force and electrostatic force calculation method as those in the step (4) are adopted in the NVT stage, the solvate system after the energy in the step (4) is minimized by using a V-rescale temperature control method, the set temperature is 300K, the running time in the process is 1ns, and the obtained structure is named as 1TD _ NVT.
(6) Controlling the pressure at 1bar and the temperature at 300K by using a Berendsen pressure control method and V-rescale temperature control, taking the structure file obtained in the step (5) as an input file, and adopting the same force field, periodic boundary conditions, van der Waals force and electrostatic force calculation methods as those in the step (4) in the NPT stage, wherein the position limitation is still consistent with that in the step (5), and the obtained structure file is 1TD _ NPT.
Wherein: after this equilibration period, the cubic box had a size of 15.3 × 15.3nm3。
(7) Entering a molecular dynamics simulation (MD) stage, removing the position constraint force applied to the nucleic acid structure in the step (6), adopting a force field, a period boundary condition, van der Waals force and electrostatic acting force which are the same as those in the step (4) for calculation, adopting a temperature control method which is the same as that in the step (5), controlling the pressure to be 1bar by using a Parrinello-Rahman pressure control method, using a Verlet neighborhood list scheme with buffering for neighborhood search, setting the updated list frequency to be 10, setting the PME grid size interval to be 0.16 nanometer, using an LINCS algorithm for constraint on all keys, setting the van der Waals interaction truncation radius to be 1nm, and carrying out 50ns molecular dynamics simulation on the system by using the time step of 2fs to obtain a structure file and a topology file which are 1TD _ md.gro, 1TD _ md.top and a track file 1TD _ md.xtc in sequence.
(8) And (3) storing 5000 steps of output results every 10ps in the dynamic MD process so as to carry out next analysis and discussion, loading the track file in the step (7) into visualization software VMD-1.9, observing the track and atom fluctuation details of the DNA tetrahedral structure in the system, and carrying out specific recording and analysis.
(9) The track file 1TD _ md.xtc is processed with the modules in Gromacs, resulting in a Root mean square deviation (Root mean square deviation) value over time for the nucleic acid molecule structure, named 1TD _ rmsd.xvg.
(10) And (3) drawing by taking the root mean square deviation value in the 1TD _ rmsd.xvg file as a vertical coordinate and the running time as a horizontal coordinate (50ns) to obtain a curve of the root mean square deviation value of the DNA tetrahedron structure along with the change of time in the whole dynamic simulation process, so that the completeness and the stability of the whole tetrahedron structure can be observed.
(11) And performing conformation analysis on the track file of the cage 1TD by adopting an analysis module in Gromacs, and developing the comparison of the space capacity or size from two spiral edges and a linker.
Example 2:
(1) the mathematical chain graph 1TD of a particular topological property is plotted using coreldaw 12 software, as shown in fig. 1, with a chain graph containing 4 branches with a number of crossings on each side of 4.
(2) From the chain-link diagram, using PolygenDNA model software, set the vertex connector to consist of 5 thymidine, and by adjusting the module parameters in the program, a DNA tetrahedral nanocage full-atom model was constructed, as shown in fig. 2, named 2td.
Wherein: the number of double helix edge twists of the DNA tetrahedral cage model obtained by construction is respectively 2, the number of atoms of the full atomic model structure is 8393 corresponding to the number of intersections of the mathematical chain graph in the step (1), the number of nucleotides forming the tetrahedral structure is 264, and the tetrahedral structure is a standard DNA tetrahedral full atomic structure.
(3) The nanocage structures were solvated using gromas 5.1.2 software, Charmm27 force field addition SPC/E solvent, forming a cubic box solvent system, adding cations (Na)+) The solvation system was kept electrically neutral and the resulting structure was named 2TD _ box _ ions.
Wherein: the number of water molecules contained in the above system was 196568, and the number of sodium ions was 260.
(4) The solvent system is treated with Energy minimization (Energy minimization) with total step size of 5000 steps by using a Steepest descnent (steeps defect), Periodic boundary conditions (Periodic boundary conditions) are used, namely pbc ═ xyz, Periodic boundaries are used in all directions to avoid real phase boundaries, the force field used is the same as that in step (3), atomic electrostatic interaction is calculated by using a Particle Mesh Ewald (PME) method, and short-range (van der waals) interaction is treated by using Lennard-Jones (L-J) potential, and the obtained structure file is sequentially named as: 2TD _ em.
Wherein: the distance of the nucleic acid structure from the water box inside the solvent system was set to 3nm in consideration of the nucleic acid structure in a state of fluctuation during the simulation.
(5) Using 1000kJ mol-1*nm-2The position limiting force is applied to all heavy atoms (Non-hydrogen atoms) in the nucleic acid structure, the same force field, periodic boundary condition and electric field force calculation method as those in the step (4) are adopted in the NVT stage, the solvate system after the energy in the step (4) is minimized is set to be 300K by using a V-cache temperature control method, the running time in the process is 1ns, and the obtained structure is named as 2TD _ NVT.
(6) Controlling the pressure at 1bar and the temperature at 300k by using a Berendsen pressure control method and V-rescale temperature control, taking the structure file obtained in the step (5) as an input file, and adopting the same force field, periodic boundary conditions, van der Waals force and electric field force calculation methods as those in the step (4) in the NPT stage, wherein the position limitation is still consistent with that in the step (5), and the obtained structure file is 2TD _ NPT.
Wherein: after this equilibration phase, the cubic box had dimensions of 18.1 × 18.1nm3。
(7) Entering a molecular dynamics simulation (MD) stage, removing the position constraint force applied to the nucleic acid structure in the step (6), adopting a force field, a period boundary condition, van der Waals force and electrostatic acting force which are the same as those in the step (4) for calculation, adopting a temperature control method which is the same as that in the step (5), controlling the pressure to be 1bar by using a Parrinello-Rahman pressure control method, using a Verlet neighborhood list scheme with buffering for neighborhood search, setting the updated list frequency to be 10, setting the PME grid size interval to be 0.16 nanometer, using an LINCS algorithm for constraint on all keys, setting the van der Waals interaction truncation radius to be 1nm, and carrying out 50ns molecular dynamics simulation on the system by using the time step of 2fs to obtain a structure file and a topology file which are 2TD _ md.gro, 2TD _ md.top and a track file 2TD _ md.xtc in sequence.
(8) And (3) storing 5000 steps of output results every 10ps in the dynamic MD process so as to carry out next analysis and discussion, loading the track file in the step (7) into visualization software VMD-1.9, observing the track and atom fluctuation details of the DNA tetrahedral structure in the system, and carrying out specific recording and analysis.
(9) The track file 2TD _ md.xtc is processed with the modules in Gromacs, resulting in a Root mean square deviation (Root mean square deviation) value over time for the nucleic acid molecule structure, named 2TD _ rmsd.xvg.
(10) And (3) drawing by taking the root mean square deviation value in the 2TD _ rmsd.xvg file as a vertical coordinate and the running time as a horizontal coordinate (50ns) to obtain a curve of the root mean square deviation value of the DNA tetrahedron structure along with the change of time in the whole dynamic simulation process, so that the completeness and the stability of the whole tetrahedron structure can be observed.
(11) And performing conformation analysis on the track file of the cage 2TD by adopting an analysis module in Gromacs, and developing the comparison of the space capacity or size from two spiral edges and a linker.
Example 3:
(1) the mathematical chain graph 1TD of a particular topological property is plotted using coreldaw 12 software, as shown in fig. 1, with a chain graph containing 4 branches with 6 intersections on each side.
(2) Pdb was constructed from the chain-link map using PolygenDNA model software, setting the vertex connectors to consist of 5 thymidine, by adjusting the module parameters in the program, and a DNA tetrahedral nanocage full-atom model was constructed, as shown in fig. 2, named 3td.
Wherein: the number of double helix edge twists of the constructed DNA tetrahedral cage model is respectively 3, which corresponds to the number of intersections of the mathematical chain graph in the step (1), the structural atomic number of the full atomic model is 11825, the number of nucleotides forming the tetrahedral structure is 372, and the tetrahedral structure is a standard DNA tetrahedral full atomic structure.
(3) The nanocage structures were solvated using gromas 5.1.2 software, Charmm27 force field addition SPC/E solvent, forming a cubic box solvent system, adding cations (Na)+) The solvation system was kept electrically neutral and the resulting structure was named 3TD _ box _ ions.
Wherein: the number of water molecules contained in the above system was 239695 and the number of sodium ions was 366.
(4) The solvent system is treated with Energy minimization (Energy minimization) with total step size of 5000 steps by using a Steepest descnent (steeps defect), Periodic boundary conditions (Periodic boundary conditions) are used, namely pbc ═ xyz, Periodic boundaries are used in all directions to avoid real phase boundaries, the force field used is the same as that in step (3), atomic electrostatic interaction is calculated by using a Particle Mesh Ewald (PME) method, and short-range (van der waals) interaction is treated by using Lennard-Jones (L-J) potential, and the obtained structure file is sequentially named as: 3TD _ em.gro.
Wherein: the distance of the nucleic acid structure from the water box inside the solvent system was set to 3.5nm in consideration of the nucleic acid structure in a state of fluctuation during the simulation.
(5) Using 1000kJ mol-1*nm-2The position limiting force is applied to all heavy atoms (Non-hydrogen atoms) in the nucleic acid structure, the same force field, periodic boundary condition and electric field force calculation method as those in the step (4) are adopted in the NVT stage, the solvate system after the energy in the step (4) is minimized is set to be 300K by using a V-cache temperature control method, the running time in the process is 1ns, and the obtained structure is named as 3TD _ NVT.
(6) Controlling the pressure at 1bar and the temperature at 300k by using a Berendsen pressure control method and V-rescale temperature control, taking the structure file obtained in the step (5) as an input file, and adopting the same force field, periodic boundary conditions, van der Waals force and electric field force calculation methods as those in the step (4) in the NPT stage, wherein the position limitation is still consistent with that in the step (5), and the obtained structure file is 3TD _ NPT.
Wherein: after this equilibration period, the cubic box had dimensions of 19.5 × 19.5nm3。
(7) Entering a molecular dynamics simulation (MD) stage, removing the position constraint force applied to the nucleic acid structure in the step (6), adopting a force field, a period boundary condition, van der Waals force and electrostatic acting force which are the same as those in the step (4) for calculation, adopting a temperature control method which is the same as that in the step (5), controlling the pressure to be 1bar by using a Parrinello-Rahman pressure control method, using a Verlet neighborhood list scheme with buffering for neighborhood search, setting the updated list frequency to be 10, setting the PME grid size interval to be 0.16 nanometer, using an LINCS algorithm for constraint on all keys, setting the van der Waals interaction truncation radius to be 1nm, and carrying out 50ns molecular dynamics simulation on the system by using 2fs time step length to obtain a structure file and a topology file which are 3TD _ md.gro, 3TD _ md.top and a track file 3TD _ md.xtc in sequence.
(8) And (3) storing 5000 steps of output results every 10ps in the dynamic MD process so as to carry out next analysis and discussion, loading the track file in the step (7) into visualization software VMD-1.9, observing the track and atom fluctuation details of the DNA tetrahedral structure in the system, and carrying out specific recording and analysis.
(9) The track file 3TD _ md.xtc was processed with a module from Gromacs, resulting in a time-varying Root mean square deviation (Root mean square deviation) value for the nucleic acid molecule structure, named 3TD _ rmsd.xvg.
(10) And (3) drawing by taking the root mean square deviation value in the 3TD _ rmsd.xvg file as a vertical coordinate and the running time as a horizontal coordinate (50ns) to obtain a curve of the root mean square deviation value of the DNA tetrahedron structure along with the change of time in the whole dynamic simulation process, so that the completeness and the stability of the whole tetrahedron structure can be observed.
(11) And performing conformation analysis on the track file of the cage 3TD by adopting an analysis module in Gromacs, and developing the comparison of the space capacity or size from two spiral edges and a linker.
The analysis of conformational results was performed by:
(1) root mean square deviation (Root mean square deviations). The dynamic change of the whole structure in the simulation process is shown, and the dynamic change is used for judging the stability of the whole DNA tetrahedral structure.
(2) Root mean square fluctuation (Root mean square fluctuation). The method is used for indicating the root mean square displacement of each nucleotide in a certain frame conformation compared with an average conformation so as to judge the flexibility of a certain region of a DNA tetrahedron.
(3) DNA helix geometric parameters (DNA helix geometric parameters). The 16 parameter values of the double helix edge of the DNA tetrahedron after the simulation is finished are calculated by using an online CURVES program, and the change state of the helix in the simulation process is reflected by comparing with the standard value.
(4) Cross-correlation map (Cross-correlation map). Reflecting the motion correlation degree of double helix edges and vertex connectors in a DNA tetrahedral structure, the invention uses MATLAB 2019 as software for part of data processing.
The results of the time-dependent RMSD curves of examples 1-3, as shown in FIG. 3, show that the nano-cages of example 1 undergo relatively small changes from the initial structure, and the RMSD values of the three portions are low. The RMSD curve values for lines 2, 3 are very close as the number of crossings increases in the other two examples 2 and 3, i.e. the double helix edge of DNA has a significant effect on the stability of the whole cage as the number of DNA twists increases, and it is also shown from the side that the DNA tetrahedron constructed by the method used in the present invention can maintain structural integrity.
The time-varying RG curves of examples 1-3, as shown in fig. 4, show that by increasing the number of crossing of the two helical edges of the tetrahedron, the RG value has smaller fluctuation, and the gyration radius value of the whole nanocage is obviously increased, wherein the average values of RG of examples 1, 2 and 3 are 3.0, 4.6 and 5.9nm, respectively, which can better illustrate that the volume of the tetrahedral nanocages constructed in examples 2 and 3 is larger than that of the tetrahedral nanocage constructed in example 1.
The results of the characterization of the RMSF of examples 1-3 with Global RMSF as shown in FIGS. 5-6, by comparison, show that the fluctuation values inside the two double helix strands are the smallest, the highest values are from the ends of the two strands, and furthermore, as the number of double helix crossings increases, the two curves of each double helix show that in the cages of examples 2 and 3, the fluctuation frequency at the junction of the vertex and the double helix edge is higher than that of example 1, which indicates that the double helix edge of DNA becomes more sensitive to conformational changes in the connector region, i.e., changes in the number of helix crossings cause changes in the flexibility at the junction of the vertices of the tetrahedron of DNA.
The cross-correlation graphs of examples 1-3 are shown in FIG. 7, and the results show that the correlation intensity values of two complementary single strands in example 3 are most distributed among the constructed DNA tetrahedral cages, while the correlation intensity values of two complementary single strands in example 2 are the weakest in example 1.
The connector clusters of examples 1-3 accumulate frequency distribution results, indicating that the conformational changes in the linker region exhibit some different behavior as the number of DNA crossovers increases. For the nanocage structure in example 1, the conformations were in the most frequently occurring cluster of three in each connector region, exceeding 50% of the simulation time. In contrast, for example 2 and example 3, most conformations expressed as the three most clusters were modeled for more than 65% and 80% of time, respectively, indicating that the conformational variability is linearly decreasing in relation to the number of DNA crossovers in the three nanocages, demonstrating that the number of DNA double helix strands crossovers can be used as an alternative method to modulate the conformational variability of the nanocages while keeping the linker length unchanged, based on the analysis results in fig. 3-7 above, demonstrating that the three DNA tetrahedral models contained in examples 1-3 are stable and have significantly increased internal spatial capacity.
According to 4 branches, 2 crosses and the total number of nucleotides designed in the embodiment 1, the number of nucleotides in each branch in a tetrahedron is 36, a nucleotide synthesizer is used for automatically synthesizing DNA branches with known number of nucleotides experimentally, and the base sequence of the DNA branches can be given by modeling software; further purifying by deformation gel electrophoresis, and then treating by DNase to obtain a DNA module capable of being used for synthesizing tetrahedrons; annealing, and detecting the information of the morphological size of the nucleic acid composition through non-denaturing gel electrophoresis to complete the construction of the DNA tetrahedral nanocage.
The invention provides a new mode for constructing a DNA tetrahedron model, expounds the number of branches, the number of crossings and the total number of nucleotides required for constructing the DNA tetrahedron model on the atomic level through embodiments, provides basic parameters required for synthesizing a DNA tetrahedron main body in the experimental process, reduces unnecessary complexity in the earlier preparation process, has important guiding significance for experimental synthesis of the DNA tetrahedron, has a unique internal cavity structure like a DNA polyhedron, and has better development prospect in the aspects of material synthesis and biological medicine carrying by virtue of the biocompatibility characteristic and editability of the DNA tetrahedron.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for obtaining stable DNA tetrahedron synthesis parameters based on modeling is characterized by comprising the following steps:
obtaining the branch number of a DNA tetrahedron and the crossing number of each edge of the DNA tetrahedron; drawing a mathematical chain ring graph according to the branch number and the cross number; constructing a DNA tetrahedral nanocage full-atom model according to the mathematical chain graph to obtain the total number of nucleotides;
carrying out solvation treatment on the DNA tetrahedral nanocage full-atom model by using Gromacs software to form a cubic box solvent system, and adding ions into the cubic box solvent system to keep the cubic box solvent system electrically neutral;
carrying out energy minimization treatment on the electrically neutral cube box solvent system by using Gromacs software to obtain a minimized structure file;
carrying out NVT stage processing by using the minimized structure file as an input file by the Gromacs software to obtain an NVT structure file;
the Gromacs software carries out NPT stage processing by taking the NVT structure file as an input file to obtain an NPT structure file;
the Gromacs software takes the NPT structure file as an input file to carry out molecular dynamics simulation phase processing to obtain an MD track file;
processing the MD track file by a module in the Gromacs to obtain a root mean square deviation value of the nucleic acid molecule structure along with the time change;
acquiring the integrity and stability of the DNA tetrahedron according to the root-mean-square deviation value and the running time;
repeating the steps to obtain the branch number, the crossing number and the total number of the nucleotides of the DNA tetrahedron with integrity and stability.
2. The method for obtaining model-based stable DNA tetrahedral synthesis parameters of claim 1, wherein the solvation process uses SPC/E solvent;
alternatively, sodium ions are added to the cube-box solvent system.
3. The method for obtaining stable DNA tetrahedral synthesis parameters based on modeling according to claim 1, wherein the method of energy minimization process is the steepest descent method;
or the total step length of the energy minimization treatment is 2000-6000 steps;
or, periodic boundary conditions are used in X, Y and Z directions in the energy minimization process;
or the distance between the nucleic acid structure in the cubic box solvent system in the energy minimization treatment and the cubic box is 2-4 nanometers.
4. The method for obtaining stable DNA tetrahedral synthesis parameters based on modeling according to claim 1, wherein in the NVT stage processing, a V-rescale temperature control method is adopted;
or, in the NVT stage processing, 500-1500 kJ mol is adopted-1*nm-2Exerts a position-limiting force on all heavy atoms in the nucleic acid structure;
or the force field, the periodic boundary condition and the electric field force calculation method adopted by the NVT stage processing are the same as those of the energy minimization processing.
5. The method for obtaining stable DNA tetrahedral synthesis parameters based on modeling according to claim 1, wherein in the NPT stage processing, the pressure and temperature are controlled by a Berendsen pressure control method and a V-rescale temperature control method respectively;
or the force field, periodic boundary condition, van der waals force and electric field force calculation method adopted by the NPT stage processing is the same as that of the minimization processing;
alternatively, the location limits of the NPT phase processing are kept consistent with the location limits of the NVT phase processing.
6. The method for obtaining stable DNA tetrahedron synthesis parameters based on modeling according to claim 1, wherein in the molecular dynamics simulation phase, the position constraint force applied to the nucleic acid structure in the NPT phase processing is removed, the force field, the periodic boundary condition, the van der Waals force and the electrostatic force calculation method adopted in the molecular dynamics simulation phase are the same as the energy minimization processing, and the temperature control method is the same as the NVT phase processing;
or in the molecular dynamics simulation stage, the pressure is controlled by adopting a Parriello-Rahman pressure control method, the atom electrostatic interaction is recorded by adopting a Particle Mesh Ewald method, all bonds are constrained by using an LINCS algorithm, and the short-range interaction is processed by adopting a Lennard-Jones potential.
7. The method for obtaining stable DNA tetrahedral synthesis parameters based on modeling according to claim 1, wherein in the molecular dynamics simulation stage, the mesh size interval is set to 0.15-0.17 nm;
or in the molecular dynamics simulation stage, the truncation radii are set to be 0.5-1.5 nm;
or in the molecular dynamics simulation stage, the molecular dynamics simulation of 45-55 ns is carried out on the system by adopting the time step of 1-3 fs.
8. The method for obtaining modeling-based stable DNA tetrahedron synthesis parameters of claim 1, wherein before the module processing, the visualization software performs record analysis on a minimized track file, an NVT track file, an NPT track file and an MD track file.
9. The method for obtaining stable DNA tetrahedral synthesis parameters based on modeling according to claim 1, wherein the analysis module in Gromacs performs conformational change analysis on nucleic acids in MD track file, and the comparison of space capacity or size is developed from two spiral edges and linker parts.
10. The method for obtaining modeling-based stable DNA tetrahedron synthesis parameters of claim 1, wherein the DNA tetrahedron is synthesized based on the number of branches, the number of intersections, and the total number of nucleotides of the DNA tetrahedron having integrity and stability.
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