Method for regulating and controlling DNA (deoxyribonucleic acid) charge transfer by small molecular medicine in covalent form

Abstract

The invention relates to a method for regulating and controlling DNA (deoxyribonucleic acid) charge transfer by a covalent small molecule drug, and belongs to the field of molecular electronics. The method aims at solving the problems that in the prior art, DNA internal charge transmission is difficult to flexibly regulate and control, and experiment repeatability is poor. According to the technical scheme, the method comprises the following steps: acquiring a drug-DNA covalent conjugate model from a PDB database and modifying the drug-DNA covalent conjugate model into a specific sequence; obtaining a stable conformation through molecular dynamics simulation; calculating the conductivity and the charge transmission rate by adopting a density functional theory and an unbalanced green function; and analyzing HOMO wave function distribution and state density to reveal a regulation rule. According to the invention, accurate and stable regulation and control of DNA charge transfer are realized, the experiment repeatability is remarkably improved, and a new way is provided for application of DNA in molecular electronic devices.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of molecular electronics, and relates to a method for regulating DNA charge transport in a covalent form. BACKGROUND

[0002] Deoxyribonucleic acid is a long-chain biomolecule formed by base pairs through π-π stacking, which naturally has a π conjugated system and can theoretically realize charge transport function, and is therefore regarded as an ideal candidate material for constructing nanoscale electronic devices, such as molecular wires and biosensors. However, in practical applications, the charge transport performance of deoxyribonucleic acid is affected by multiple factors such as sequence specificity, spatial conformation and environmental factors, resulting in instability of the charge transport of natural deoxyribonucleic acid and difficulty in precise regulation. Therefore, how to realize stable regulation of deoxyribonucleic acid charge transport has become a key problem to be solved in the technical field.

[0003] In the prior art, researchers have tried to realize the regulation of deoxyribonucleic acid charge transport through various technical paths, such as realizing global regulation by changing temperature, ion strength and other environmental conditions, or realizing random regulation by means of non-specific chemical modification. However, these methods generally have obvious limitations and are difficult to realize flexible and stable regulation for specific deoxyribonucleic acid fragments or specific sites. Further analysis shows that due to the limitation of technical means and the introduction of too many approximations in the modeling process, existing researches are often difficult to draw clear and unified conclusions. The diversity of the conclusions is highly related to the differences in experimental systems and different modeling methods, which also highlights the necessity of carrying out continuous and systematic research on this problem.

[0004] In recent years, it has been found that after small molecule drugs form covalent combination with deoxyribonucleic acid, they can fix the position and produce new highest occupied molecular orbital energy level distribution, and this distribution is not affected by the base sequence, thereby providing a relatively stable method for modulating the charge transport rate of deoxyribonucleic acid. Small molecule drugs have the characteristics of small molecular weight, mostly artificial chemical synthesis, and clear and controllable chemical structure. The interaction between small molecule drugs and deoxyribonucleic acid exists in multiple forms, mainly including intercalation combination, groove combination and covalent combination. Existing researches have shown that the action of small molecule drugs can change the stacking structure of local π bonds of deoxyribonucleic acid, and further affect the charge transport characteristics inside the molecule. This discovery provides a new technical path for controllable modulation of deoxyribonucleic acid charge transport, which is helpful to realize molecular electronic devices based on deoxyribonucleic acid, and can also develop biosensors based on this, providing important application value for disease diagnosis and biological monitoring. SUMMARY

[0005] Therefore, the present application aims to provide a method for regulating DNA charge transport by covalent small molecule drugs.

[0006] To achieve the above-mentioned purpose, the present application provides the following technical solutions.

[0007] A method for regulating DNA charge transport by covalent small molecule drugs, comprising the following steps:

[0008] (a) obtaining the original model of drug-DNA covalent conjugate from Protein Data Bank (PDB) and modifying it into two specific DNA sequences;

[0009] (b) wrapping the drug-DNA covalent conjugate molecule prepared in step (a) with an octahedral water box, and adding sodium ions (Na + ) to neutralize the negative charge of DNA phosphate residues, so that the system is electrically neutral, and loading the force field of small molecule drugs, the force field of DNA, the force field of solvent and the force field of ions, respectively;

[0010] (c) finding the local optimal conformation of the molecule by energy minimization of the system in step (b), and then heating the system to 300K for 5 nanoseconds (ns) of stable simulation and 10 ns of sampling simulation;

[0011] (d) extracting the optimal molecular conformation of all molecules in step (c), and calculating the conductivity and charge transport rate thereof by using Density Functional Theory (DFT) and Non-Equilibrium Green's Function (NEGF) formula;

[0012] (e) according to the calculation results of step (d) and the Highest Occupied Molecular Orbital (HOMO) wave function distribution and Density of States (DOS) distribution of the molecule, analyzing the influence law of different small molecule drugs on DNA charge transport, and realizing the regulation of DNA charge transport by covalently combining different drug molecules.

[0013] Further, the small molecule drug in step (a) is one of Anthramycin, Tamoxifen, 2,7-Diaminomitosene and PT-ACRAMTU, and the DNA sequence is modified to 5'-TTGGGTT-3' or 5'-GCAGTGC-3', and the small molecule drug is covalently combined with the guanine (G) base in the middle of the DNA sequence.

[0014] Further, the size of the octahedral water box in step (b) is larger than the size of the covalent conjugate, and the number of added Na+ions is 12.

[0015] Further, the specific steps of energy minimization in step (c) are: first, constrain the conjugate molecule, optimize the water box by 500 steps of steepest descent method and 500 steps of conjugate gradient method, then release the constraint of the conjugate molecule, and optimize by 2500 steps of steepest descent method and 2500 steps of conjugate gradient method again, and the system temperature is maintained by Langevin dynamics method.

[0016] Further, in step (d), the Fock matrix and the overlap matrix (Overlap Matrix) of the system are obtained by using B3LYP density functional and 6-31G(d,p) basis set to generate the Hamiltonian, and the Büttiker probe is introduced in the non-equilibrium Green's function to consider the influence of quantum decoherence.

[0017] Further, in step (d), the retarded Green's function in the non-equilibrium Green's function formula is represented as:

[0018]

[0019] wherein E is energy, I is unit matrix, H is the Hamiltonian of the molecule, and are the self-energy matrices of the left and right connection points, respectively, and B is the self-energy matrix introduced by the Büttiker probe.

[0020] Further, in step (d), the calculation formula of the charge transport probability T eff is:

[0021]

[0022] wherein L is the coupling between the left electrode and the contact point, Γ R is the coupling between the right electrode and the contact point, G a is the advanced Green's function, N b is the number of Büttiker probes, and W ij is represented as:

[0023] W ij = [(1-R ii )δ ij -Γ i G r Γ j G a (1-δ ij)

[0024] R ii is the reflection probability at the probe i.

[0025] Further, the calculation formula of the conductance G(E f ) in step (d) is as follows:

[0026]

[0027] wherein G0 is the quantum conductance, and the value is 7.75 x 10 -5 S, E f is the Fermi energy level.

[0028] Further, the calculation formula of the DOS in step (e) is as follows:

[0029]

[0030] wherein G(E f ) is the Green function at the Fermi energy level, and Im(G(E f )) represents the imaginary part of G(E f ).

[0031] Based on the method for regulating the DNA charge transport by the covalent form of small molecule drugs, the method is used for evaluating the regulation of the DNA charge transport by the covalent form of small molecule drugs.

[0032] The present application has the following beneficial effects:

[0033] (1) The traditional regulation method often depends on changing the environmental factors such as temperature or ionic strength, and can only realize the global and non-specific regulation. However, the present application can realize the accurate regulation for the specific fragment and specific site of DNA by selecting the specific small molecule drugs to covalently combine with DNA, and significantly improves the accuracy and flexibility of the regulation.

[0034] (2) In the prior art, the DNA charge transport is greatly affected by the sequence, conformation, environment and other factors, and the experimental results are often difficult to repeat. The present application uses the covalent binding method to firmly anchor the small molecule drugs at the specific position of DNA, forms a stable drug-DNA complex, effectively avoids the instability caused by non-specific binding, and ensures the reliability and repeatability of the experimental results.

[0035] (3) The present application combines molecular dynamics simulation and quantum chemical calculation method, and for the first time systematically clarifies the rules of different small molecule drugs changing the highest occupied molecular orbital distribution and state density distribution of DNA through covalent binding, and provides an in-depth theoretical basis for understanding the drug-DNA interaction.

[0036] (4) The regulation method established by this invention can select different drug molecules to achieve customized regulation of the electrical properties of DNA according to actual needs, providing a new technical approach for the development of DNA-based molecular wires, biosensors and other nanoelectronic devices.

[0037] (5) The four small molecule drugs used in this invention represent different binding modes and spatial configurations, and the established method can be extended to other small molecule drug systems. At the same time, the method is not limited by DNA base sequences and is applicable to different types of DNA sequences, demonstrating good versatility.

[0038] (6) By studying the effect of the interaction between small molecule drugs and DNA on their electrical properties, we can not only help to understand the mechanism of drug action, but also provide new research directions for the development of disease diagnosis and biomonitoring technologies based on electrical signals.

[0039] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Attached Figure Description

[0040] To make the objectives, technical solutions, and advantages of the present invention clearer, the preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings, wherein:

[0041] Figure 1 The diagrams in the middle show two standard B-type DNA sequences.

[0042] Figure 2 In the image, (a) and (b) are a three-dimensional molecular model of the anthramycin drug-DNA covalently bound and a two-dimensional diagram of the drug molecule, respectively.

[0043] Figure 3 In the middle (a) and (b), respectively, are the three-dimensional molecular model of the Tamoxifen drug-DNA covalent compound and the two-dimensional diagram of the drug molecule;

[0044] Figure 4 In the image, (a) and (b) are a three-dimensional molecular model of the 2,7-Diaminomitosene drug-DNA covalently bound compound and a two-dimensional diagram of the drug molecule, respectively.

[0045] Figure 5 In the middle (a) and (b), respectively, are the three-dimensional molecular model of the PT-ACRAMTU drug-DNA covalently bound compound and the two-dimensional diagram of the drug molecule;

[0046] Figure 6In the diagram, (a), (b), (c), and (d) represent the electrical conductivities of two different sequences of four drug-DNA covalently bound compounds, respectively.

[0047] Figure 7 In the figures (a), (b), (c), and (d), the charge transport rates of two different sequences of four drug-DNA covalent conjugates are shown. Detailed Implementation

[0048] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that the illustrations provided in the following embodiments are only schematic representations of the basic concept of the present invention. Unless otherwise specified, the following embodiments and features can be combined with each other.

[0049] The accompanying drawings are for illustrative purposes only and are schematic diagrams, not actual pictures. They should not be construed as limiting the invention. To better illustrate the embodiments of the invention, some parts in the drawings may be omitted, enlarged, or reduced, and do not represent the actual product dimensions. It is understandable to those skilled in the art that some well-known structures and their descriptions may be omitted in the drawings.

[0050] In the accompanying drawings of the embodiments of the present invention, the same or similar reference numerals correspond to the same or similar components. In the description of the present invention, it should be understood that if terms such as "upper," "lower," "left," "right," "front," and "rear" indicate the orientation or positional relationship based on the orientation or positional relationship shown in the drawings, they are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, the terms used to describe positional relationships in the drawings are only for illustrative purposes and should not be construed as limiting the present invention. For those skilled in the art, the specific meaning of the above terms can be understood according to the specific circumstances.

[0051] Please see Figures 1-7 Molecular dynamics simulation analysis and charge transport calculations for four small molecule drug-DNA covalent bonds—Anthramycin, Tamoxifen, 2,7-Diaminomitosene, and PT-ACRAMTU—included the following steps:

[0052] (1) The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of the 10 ns sampled simulation data were analyzed using the CPPTRAJ tool. RMSD represents the fluctuation deviation between the reference structure and the simulation structure in each frame, in units of 10 ns. When RMSD = 0.0, it indicates that the reference structure and the simulation structure perfectly overlap. RMSD is defined as:

[0053]

[0054] Where N is the number of atoms, m i Let X be the mass of the i-th atom. i Y is the coordinate vector of the target atom i. i This is the coordinate vector of reference atom i, and M is the total mass. If the RMSD is not mass-weighted, then all m i Both are 1, and M = N.

[0055] (2) Calculate the position fluctuation (also known as root mean square fluctuation, RMSF) of a specified atom. The formula for calculating the RMSF of a given atom i is:

[0056]

[0057] Here, x represents the atom position, and these average values ​​are calculated for all input frames.

[0058] (3) The molecular structure for DFT calculations was taken from the frame with the lowest internal energy in the 10 ns sampling of the molecular dynamics simulation to ensure the stability of the complex molecular structure to the greatest extent. After removing water molecules and counterions from the model, single-point energy calculations were performed using G09 to obtain the Fock and Overlap matrices of the complex. Due to the large molecular structure, the B3LYP density functional and the 6-31G(d,p) basis set were selected for DFT calculations. Since the counterion Na+ was removed, the charge of the complex is equal to the charge of the phosphate group in DNA, and a polarized continuum model was used for the water solvent.

[0059] (4) This invention employs a decoherent charge transport model to calculate molecular charge transport. The metal electrode is coupled to the 5' ends of the two chains via bridging groups. In the subsequent Green's function, the contact coupling between the molecule and the two electrodes is set to 100 meV to simulate the influence of the electrodes. The Fock matrix and Overlap matrix obtained from the DFT calculation are then... Orthogonal transformations are used to generate the system's Hamiltonian matrix. Then, the charge transport in the molecular system is calculated using the non-equilibrium Green's function formula with decoherence. The delayed Green's function can be expressed as:

[0060]

[0061] Where E is energy, I is the identity matrix, and H is the Hamiltonian of the molecule. and These are the self-energy matrices of the left and right join points, respectively. ∑ B This represents the self-energy matrix generated by the Büttiker probe, which is used to introduce decoherence into the system. Here, the decoherence rate is set to 10 meV.

[0062] The formula for calculating the charge transport probability is:

[0063]

[0064] Where Γ L It is the coupling between the left electrode and the contact point, Γ R It is the coupling between the right electrode and the contact point, G r It is the delayed Green's function, G a It is a higher-level Green's function, N b This represents the number of Büttiker probes. It is W ij The reverse, W ij =[(1-R ii )δ ij -Γ i G r Γ j G a (1-δ ij )], R ii This is the reflection probability at probe i. With T... eff The parameters can be used to calculate the conductance, as shown in the following formula:

[0065]

[0066] Where E f G is the Fermi function, and G0 is the quantum conductance (G0 = 2e² / h ≈ 7.75 × 10⁻⁵ S).

[0067] The DOS value can be further calculated using the following formula:

[0068]

[0069] Where a is the number of all relevant atomic orbitals, Im(G(E) f )) represents G(E f The imaginary part of ).

[0070] Example 1

[0071] First, the electrical properties of standard B-type DNA were calculated. The specific steps are as follows:

[0072] (1) Model Construction: First, standard B-type DNA with sequences 5`-TTGGGTT-3` and 5`-GCAGTGC-3` was constructed using a nucleic acid sequence three-dimensional structure construction tool. The PDB file generated by the tool was opened with GaussView, and the B3LYP functional and 6-31G(d,p) basis set were selected, with charge and spin multiplicity of -12 and 1, respectively. A polarized continuum model was used for the aqueous solvent to generate a gjf file.

[0073] (2) The molecular structure of the gjf file generated by GaussView is calculated by DFT using G09 to obtain the energy level information of the molecules of the system as well as the Fock matrix and Overlap matrix. Then, the non-equilibrium Green's function method with decoherence is executed using Python and Matlab scripts to calculate the electrical properties of the molecules such as conductivity and charge transport rate.

[0074] (3) Calculation of electrical signal-related parameters: This method was used to calculate the electrical properties of two sequences of standard B-type DNA. The HOMO level of the stacked G sequence was -4.86 eV, the lowest unoccupied molecular orbital (LUMO) level was -0.81 eV, and the band gap was 4.05 eV; the conductivity was 1.22 × 10⁻⁶. -6 G0, charge transport rate is 1.45 × 10 -6 The alternating G sequence has a HOMO level of -5.07 eV, a LUMO level of -0.73 eV, and a band gap of 4.34 eV; its conductivity is 5.26 × 10⁻⁶. -6 G0, charge transport rate is 8.09 × 10 -6 .

[0075] Example 2

[0076] (1) Model Construction: Four original models of small molecule drugs covalently bound to DNA were downloaded from the RCSB:PDB database: 274D, 1FJ5, 1JO1, and 1XRW. The DNA sequences of the original models were modified to 5'-TTGGGTT-3' and 5'-GCAGTGC-3' using the 3D visualization software pyMOL, to facilitate comparative studies with the standard B-type DNA of the aforementioned non-covalently bound drugs. This resulted in eight drug-DNA covalently bound molecular models. The modified PDB format files were uploaded to the server for simulation and calculation.

[0077] (2) Molecular dynamics simulation method: The pdb4amber tool in the Amber toolkit was used to organize the contents of the pdb file. The charge of the drug molecule was calculated, and its force field file was generated, including information such as bond length, bond angle, and dihedral angle. The tleap tool was used to load the force fields of DNA molecules, drug molecules, water molecules, and ions respectively. An octahedral water box was used to enclose the DNA molecule, and Na+ ions were added to make the entire system electrically neutral. The topology file and coordinate file were saved. Before the formal simulation, the steepest descent method and the conjugate gradient method were used to minimize the energy of the molecular structure to release the structural tension inside the molecule. Then the molecular system was heated to 300K. A 5ns equilibrium simulation was performed to stabilize the entire system. Finally, a 10ns sampling simulation was performed to observe and analyze the fluctuation of the drug-DNA covalent conjugate in the aqueous solvent.

[0078] (3) Simulation results show that the maximum difference in root mean square deviation (RMSD) of all complexes is within the range of to Within this range, it is evident that they all converge to [the initial conformation]. The fluctuations were small, and the molecules exhibited relatively stable behavior in aqueous solutions. Observations of conformational changes during a 10ns sampling simulation revealed that, aside from the wobble of the two end bases, the other bases (or drug molecules) remained relatively stable, and no hydrogen bond breakage occurred near the drug molecules. Furthermore, the conformation of standard B-type DNA was distorted to some extent due to the influence of the drug molecules, with all drug-DNA covalent bonds showing a decrease in torsion angle.

[0079] (4) Use G09 to perform DFT calculation on the molecular structure of the gjf file generated by GaussView to obtain the molecular energy level information, Fock matrix and Overlap matrix of the system. Then use Python and Matlab scripts to execute the non-equilibrium Green's function method with decoherence to calculate the electrical properties of the molecule such as conductivity and charge transport rate.

[0080] (5) Calculation of electrical signal-related parameters: Each small molecule drug has a different effect on the conductivity and charge transport rate of DNA. The charge transport rate of the stacked G sequence anthramycin drug-DNA covalent conjugate at the HOMO was reduced by 28.5% compared to the uncovalent drug stacked G sequence. Alternating G sequences showed similar performance, but with a larger variation, with the charge transport rate at the HOMO being reduced by 75.85% compared to the uncovalent drug alternating G sequence. The changes in charge transport rate were similar, with the stacked G and alternating G sequences of the anthramycin drug-DNA covalent conjugate decreasing by 37.75% and 83.95%, respectively. In addition, the conductivity and charge transport rate of the stacked G sequence tamoxifen drug-DNA covalent conjugate decreased by 55.47% and 61.68%, respectively, while those of the alternating G sequence tamoxifen drug-DNA covalent conjugate decreased by 88.47% and 92.04%, respectively. The conductivity of 2,7-Diaminomitosene drug-DNA covalently bound with stacked G sequences decreased by 45.85%, and the charge transport rate decreased by 53.96%. Alternating G sequences showed an even greater reduction in conductivity (85.18%) and charge transport rate (90.33%). The conductivity of PT-ACRAMTU drug-DNA covalently bound with stacked and alternating G sequences decreased by 47.83% and 84.45%, respectively, while their charge transport rates decreased by 55.98% and 91.07%, respectively. In general, covalent bonding of small molecule drugs tends to reduce the conductivity and charge transport rate of B-type DNA, albeit to varying degrees. Furthermore, because the alternating G sequences of uncovalent drugs inherently have higher conductivity and charge transport rates than the stacked G sequences of uncovalent drugs, the effect of drug covalent bonding is more pronounced.

[0081] Example 3

[0082] (1) Study on the HOMO wavefunction distribution of molecules: To further explore the reasons for the decrease in DNA charge transport rate due to the covalent effect of small molecule drugs, we used DFT calculations of single-point energies to analyze the HOMO wavefunction distribution of molecules for all molecular models. The HOMO of standard B-type DNA in both sequences is mainly distributed on the G bases, while the HOMO of base pairs tends to be distributed on a single base. For example, the HOMO of G:C base pairs is more distributed on the G bases. Because A:T base pairs have a higher ionization potential, consecutive A:T base pairs in stacked G sequences may have a certain hindering effect on charge transport, resulting in lower conductivity and charge transport rate of stacked G sequence DNA compared to alternating G sequences. The HOMO wavefunction distribution of eight drug-DNA covalent bonds shows that, compared to standard B-type DNA, both stacked G sequences and alternating G sequences introduce new HOMOs through covalent binding of small molecule drugs. Anthramycin and Tamoxifen, both drug-DNA covalent conjugates, are covalently bound to the N2 site of guanine and anchored in the minor groove of DNA. Their HOMO (Homologous Occurrence Modulation) is primarily distributed on the guanine covalently bound to the drug molecule, with only a portion of the HOMO distributed on the drug molecule itself. In contrast, 2,7-Diaminomitosene and PT-ACRAMTU, both drug-DNA covalent conjugates, are covalently bound to the N7 site of guanine and anchored in the major groove of DNA. Their HOMO is entirely distributed on the drug molecule itself. This indicates that covalently binding drug molecules at the bases can significantly alter the HOMO distribution of DNA, and that lower delocalization occurs after covalent binding, which may explain the decrease in molecular conductivity and charge transport.

[0083] (2) Study on the two-dimensional density of states (2D DOS) of molecules: The two-dimensional density of states distribution and HOMO wavefunction distribution of standard B-type DNA of both sequences are similar, mainly clustered on G:C. Because the alternating G sequence DNA has more G:C base pairs, its HOMO distribution has higher delocalization, including its adjacent energy levels almost spanning the entire DNA chain. In addition, observing the two-dimensional DOS distribution of all drug-DNA covalent conjugates, the new HOMOs are mainly clustered on single base pairs (or drug molecules). The HOMOs of the Anthramycin and Tamoxifen drug-DNA covalent conjugates are mainly clustered on the G bases covalently bound to the drug molecules. Conversely, the HOMOs of the 2,7-Diaminomitosene and PT-ACRAMTU drug-DNA covalent conjugates are clustered on the drug molecules. This may be related to the presence of drug molecules in the major or minor grooves of DNA, and the change in HOMO distribution caused by the covalent binding of drug molecules is independent of the DNA base sequence.

[0084] In summary, the covalent binding of the four small molecule drugs reduced the charge transport rate of standard B-type DNA to varying degrees and introduced new HOMO and LOMO energy levels, thus narrowing the energy gap. Furthermore, regardless of whether the G sequences were stacked or alternating, the covalent binding of the small molecule drugs changed the HOMO distribution of DNA, causing HOMOs that were originally distributed on multiple guanine molecules to aggregate onto the drug molecule or its covalently bound guanine molecules.

[0085] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for regulating DNA charge transport by a covalently substituted small molecule drug, characterized in that: Includes the following steps: (a) Obtain the original model of the drug-DNA covalent conjugate from the protein database PDB and modify it to two specific DNA sequences; (b) Encapsulate the drug-DNA covalently bound molecule prepared in step (a) using an octahedral water box and add sodium ions (Na+) to the system. + To neutralize the negative charge carried by DNA phosphate residues, the system is made electrically neutral, and the force fields of the small molecule drug, DNA, solvent, and ions are applied respectively. (c) Find the local optimal conformation of the molecule in the system of step (b) by minimizing energy, and then heat the system to 300K and perform a 5-nanosecond (ns) stabilization simulation and a 10-ns sampling simulation. (d) Extract the optimal molecular conformation of all molecules in step (c) and calculate their conductivity and charge transport rate using density functional theory (DFT) and non-equilibrium Green's function (NEGF) formula. (e) Based on the calculation results of step (d) and the distribution of the highest occupied molecular orbital (HOMO) wavefunction and the density of states (DOS) distribution of the molecule, analyze the influence of different small molecule drugs on DNA charge transport, and regulate DNA charge transport by covalently binding different drug molecules.

2. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 1, characterized in that: The small molecule drug in step (a) is one of Anthramycin, Tamoxifen, 2,7-Diaminomitomycin, and PT-ACRAMTU, and the DNA sequence is modified to 5'-TTGGGTT-3' or 5'-GCAGTGC-3', with the small molecule drug covalently bound to the guanine G base in the middle of the DNA sequence.

3. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 1, characterized in that: The octahedral water box described in step (b) is larger than the size of the covalently bonded compound, and the added Na... + The number of ions is 12.

4. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 1, characterized in that: The specific steps for minimizing energy in step (c) are as follows: First, constrain the bound molecules and optimize the water box using the steepest descent method and the conjugate gradient method for 500 steps. Then, remove the constraint on the bound molecules and optimize again using the steepest descent method and the conjugate gradient method for 2500 steps. The system temperature is maintained by the Langevin dynamics method.

5. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 1, characterized in that: In step (d), the Fock matrix and overlap matrix of the system are obtained using the B3LYP density functional and the 6-31G(d,p) basis set to generate the Hamiltonian, and a Büttiker probe is introduced into the nonequilibrium Green's function to account for the effects of quantum decoherence.

6. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 1, characterized in that: The delayed Green's function in the non-equilibrium Green's function formula described in step (d) Represented as: Where E is energy, I is the identity matrix, and H is the Hamiltonian of the molecule. and These are the self-energy matrices of the left and right join points, respectively, ∑ B Let be the self-energy matrix introduced by the Büttiker probe.

7. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 6, characterized in that: In step (d), the charge transfer probability T eff The calculation formula is: Among them, Γ L It is the coupling between the left electrode and the contact point, Γ R It is the coupling between the right electrode and the contact point, G a For higher-order Green's functions, N b W represents the number of Büttiker probes. ij Represented as: W ij =[(1-R ii )d ij -C i G r C j G a (1-d ij )] R ii Let be the reflection probability at probe i.

8. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 7, characterized in that: In step (d), the conductance G(E) f The formula for calculating ) is: Where G0 is the quantum conductance, with a value of 7.75 × 10⁻⁶. -5 S, E f It is the Fermi level.

9. The method for regulating DNA charge transport by a covalently converted small molecule drug according to claim 1, characterized in that: The formula for calculating DOS in step (e) is: Among them, G(E f ) is the Green's function at the Fermi level, Im(G(E) f )) represents G(E f The imaginary part of ).

10. A method for regulating DNA charge transport by a small molecule drug in covalent form according to any one of claims 1 to 9, characterized in that: The method described above is used to evaluate the regulatory effect of covalently formulated small molecule drugs on DNA charge transport.

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