Automated simulation method for self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology

Abstract

The application discloses a kind of high polymer nanometer material self-assembly crosslinking process automation simulation method based on coarse-grained simulation technology, comprising: (1) simulate high polymer self-assembly, obtain high polymer nanometer material model;(2) identify the coarse-grained mapping of crosslinking agent molecule, topological structure parameter to set up crosslinking agent coarse-grained model;(3) replace solvent beads with crosslinking agent according to topological structure parameter random search, to construct high polymer nanometer material-crosslinking agent mixed solution model;(4) identify crosslinking process information and carry out crosslinking simulation based on nearest neighbor bonding principle, finally obtain target crosslinking high polymer nanometer material model.The present application fully considers the characteristics of high polymer self-assembly, the steric hindrance restriction existing in the crosslinking process of large size material and the topological characteristics of crosslinking agent itself, improves the simulation degree of DPD simulation, and has important guiding significance for studying the microcosmic dynamics behavior of crosslinking high polymer nanometer material crosslinking process.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of high polymer self-assembly cross-linking process, and particularly relates to a high polymer nanomaterial self-assembly cross-linking process automatic simulation method based on coarse-grained simulation technology. BACKGROUND

[0002] In recent years, high polymer nanomaterials such as polymer micelles, liposomes, gels and the like have attracted extensive attention due to their special physicochemical properties. However, as a self-assembly system, the problem that the system is prone to instability in a complex application environment has always hindered the practical application of high polymer nanomaterials. Therefore, researchers have proposed a cross-linking strategy to improve the system stability. At present, the cross-linking means mainly adds a small molecule cross-linking agent with dynamic chemical bonds to the high polymer nanomaterial and performs a reaction with a catalyst, and finally purifies to obtain the cross-linked high polymer nanomaterial. However, due to the size of the high polymer nanomaterial being in the nanometer range, the current experimental technology cannot clearly show the micro-kinetic behavior of the cross-linking process of the high polymer nanomaterial, and further cannot explore the influence of the cross-linking strategy on the structural stability of the high polymer nanomaterial.

[0003] Dissipative particle dynamics (DPD) simulation has been proved to be a powerful tool to reflect the self-assembly behavior and structure-property relationship of high polymer aggregates, and can make up for the deficiency of experimental detection technology to a certain extent. For example, DPD simulation has been successfully used to construct pH-sensitive block copolymer cross-linked micelles and study the drug release mechanism under acidic conditions. However, there is still a big difference between the current DPD simulation-based cross-linking process and the actual experimental process. The existing technology is based on the simultaneous occurrence of the high polymer self-assembly process and the cross-linking process of the small molecule cross-linking agent, while the actual preparation process of the cross-linked high polymer nanomaterial usually forms aggregates first, and then further improves the structural stability of the drug delivery system through the cross-linking strategy. Moreover, since the system density needs to be strictly maintained in the DPD simulation process, the current DPD simulation of the cross-linked high polymer nanomaterial cannot realize the self-assembly first and then the addition of the cross-linking agent, because the additional addition of the cross-linking agent will change the density of the simulation system, resulting in distortion of the DPD calculation. Therefore, the simulation method of the existing technology ignores the spatial steric hindrance restriction existing between the high polymer self-assembly characteristics and the cross-linking process after the formation of the high polymer aggregates, and therefore cannot provide accurate and suitable theoretical support for clarifying the micro-kinetic behavior of the cross-linking process of the cross-linked high polymer nanomaterial and exploring the influence of the cross-linking strategy on the structural stability of the cross-linked high polymer nanomaterial. SUMMARY

[0004] The main purpose of the present application is to overcome the shortcomings and deficiencies of the prior art, and to provide a high polymer nanomaterial self-assembly cross-linking process automatic simulation method based on coarse-grained simulation technology, which can efficiently simulate the cross-linking process of the cross-linked high polymer nanomaterial from a micro perspective and provide theoretical guidance for the design and structure controllable construction of the cross-linked high polymer nanomaterial in experiments.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] On the one hand, the present invention provides a method for simulating the cross-linking process of self-assembly of polymer nanomaterials based on coarse-grained simulation technology, comprising the following steps:

[0007] S1. The pre-established polymer mixed solution model is subjected to the first step of DPD simulation of polymer self-assembly to obtain a polymer nanomaterial model; at the same time, the solvent beads of the polymer nanomaterial model are classified, and the amount of crosslinker used is calculated based on the number of crosslinking sites and components in the polymer material;

[0008] S2, identifying the coarse-grained mapping and topological structure parameters of the cross-linker molecules to establish a coarse-grained model of the cross-linker;

[0009] S3, randomly selecting the solvent beads classified in step S1, searching for adjacent solvent beads in the polymer nanomaterial model according to the coordinates of the topological structure parameters obtained in step S2 to replace the crosslinker molecules, repeating the crosslinker molecule replacement until the target replacement amount is reached, and performing the second step DPD simulation to obtain the polymer nanomaterial-crosslinker mixed solution model;

[0010] S4. Identify and classify the cross-linking sites of the polymer material and the cross-linker in the polymer nanomaterial-cross-linker mixed solution model, and perform geometric optimization and the third-step DPD simulation, search for coarse-grained bead pairs of cross-linking sites that meet the bonding distance threshold and add harmonic constraints, continue to perform the fourth-step DPD simulation, analyze the virtual bond length of the simulated cross-linked bead pairs and the end-to-end distance of the cross-linker to complete the confirmation of the cross-linking reaction process, and perform the fifth-step DPD simulation to obtain the structure of the optimized cross-linked polymer nanomaterial model; finally, through multiple cycles of the above-mentioned geometric optimization, third-step DPD simulation, fourth-step DPD simulation, bonding analysis and fifth-step DPD simulation until the target cross-linking degree is reached, the final cross-linked polymer nanomaterial model is obtained.

[0011] As a preferred technical solution, the number of steps of the first DPD simulation in step S1 is 150,000; the solvent beads for classifying the polymer nanomaterial model are to record the coordinates of all solvent beads in the model and establish a set Set1; the calculation of the amount of cross-linking agent used is obtained by identifying the total number of cross-linking sites in the polymer material and the input target cross-linking degree.

[0012] As a preferred technical solution, in step S2, the coarse-grained mapping and topological structure parameters of the cross-linker molecules are identified to establish a coarse-grained model of the cross-linker, specifically:

[0013] S21, coarse-graining mapping of the crosslinker molecules, and naming the resulting crosslinker coarse-grained beads as A, B, … according to the bonding sequence;

[0014] S22, parameterizing the three-dimensional coordinates of other components according to the crosslinker topology structure, with component A (a, b, c) as the starting point, and the parameterization rules being:

[0015] (a ± r1cosα1± r2cosα2± … ± r n cosα n ,b ± r1sinα1± r2sinα2± … ± r n sinα n ,c ± r1sinβ1± r2sinβ2± … ± r n sinβ n )

[0016] wherein r1, r2, … r n are bond lengths; α, α1, … α n are the angles between the y-axis and the x-axis; β1, … β n are the angles between the z-axis and the xy-plane.

[0017] As a preferred technical solution, in step S3, the coordinates of the topology structure parameters obtained in step S2 are used to search for the nearest solvent beads in the model of the polymeric nanomaterial, and the method of replacement is as follows: a solvent bead in Set1 is randomly selected, the coordinates of the selected solvent bead are defined as component A of the crosslinker, the coordinates of the virtual points of the remaining components are calculated one by one according to the coordinates of the topology structure parameters of the crosslinker, and the presence of solvent beads near the virtual points is screened one by one by comparing the coordinates in Set1. After all components are successfully screened and the corresponding coordinates of the solvent beads in Set1 are deducted, the virtual point position is added with a component solvent bead, and the crosslinker molecule coarse-grained model is connected and counted. If no solvent bead is screened in the search range for any component, the replacement is cancelled, and a solvent bead is randomly selected for cyclic operation. After the process of replacing the solvent beads with crosslinker solvent beads is completed, the second step of DPD simulation is performed, and the number of steps of the second step of DPD simulation is 10000 steps, and the mixed solution model of the polymeric nanomaterial-crosslinker is obtained in the relaxed structure.

[0018] wherein the virtual point only represents coordinates, and the rule for screening solvent beads near the virtual point is within the space from the virtual point.

[0019] As a preferred technical solution, the search method for the crosslinking sites of the polymeric material and the crosslinker in step S4 is as follows:

[0020] The coarse-grained bead pair of the cross-linking site in the high polymer material is uniformly set as R1, and the coarse-grained bead pair of the cross-linking site in the cross-linking agent coarse-grained model is uniformly set as R2; meanwhile, multiple cross-linking agents are also supported, at which time the coarse-grained bead pair of the cross-linking site in the high polymer material is uniformly set as R 3,5 , and the coarse-grained bead pair of the cross-linking site in the cross-linking agent molecule is uniformly set as R 4,6 ;

[0021] Among them, the cross-linking site of the cross-linking agent coarse-grained model is identified and classified, and each cross-linking agent coarse-grained model is also numbered and classified into the uncross-linked cross-linking agent set Set2.

[0022] As a preferred technical solution, the geometric optimization and the third step DPD simulation in the step S4 search for the cross-linking site bead pairs that meet the bonding distance threshold, specifically:

[0023] The step number of the third step DPD simulation is 2000; for a single cross-linking agent system, the distances of all R1 bead pairs and R2 bead pairs are calculated, the bead pairs with a distance less than the bonding distance threshold are marked and classified into the pseudo-cross-linking bead pair set Set3 for subsequent calculation; meanwhile, the cross-linking agent coarse-grained model involved is classified into the pseudo-cross-linking cross-linking agent set Set4 and eliminated from Set2; for a multiple cross-linking agent system, the calculation, screening and classification into the corresponding set are completed one by one according to the method of the single cross-linking agent system for subsequent calculation.

[0024] As a preferred technical solution, the setting of the Harmonic constraint in the step S4 is realized by an elastic coefficient k, which is set to 0.032.

[0025] As a preferred technical solution, the fourth step DPD simulation is continued in the step S4 to analyze the virtual bond length of the pseudo-cross-linking bead pair and the end-to-end distance of the cross-linking agent to complete the cross-linking reaction process confirmation, specifically:

[0026] The step number of the fourth step DPD simulation is 15000; the analysis of the virtual bond length of the pseudo-cross-linking bead pair is to analyze whether the virtual bond length of the pseudo-cross-linking bead pair in Set3 before and after the fourth step DPD simulation is less than the cutoff radius, to judge whether the pseudo-cross-linking bond is stable, and then to decide the bonding situation; the bead pairs that do not meet the condition are eliminated from Set3, and the corresponding cross-linking agent coarse-grained model is eliminated from Set4 and re-added to Set2.

[0027] The calculation of the end-to-end distance of the cross-linking agent is to calculate the end-to-end distance of the cross-linking agent coarse-grained model in Set2 and Set4 respectively, to judge the rationality of the cross-linking process, and the end-to-end distance of the two groups does not exceed 0.1 nm.

[0028] As a preferred technical solution, the step S4 is realized by the fifth step DPD simulation, and the number of simulation steps is 5000. As a preferred technical solution, the step S4 is realized by repeatedly performing the above-mentioned geometric optimization, the third step DPD simulation, the fourth step DPD simulation, the bonding analysis and the fifth step DPD simulation until the target cross-linking degree is reached. If, under the condition of a specified bonding distance threshold, the cross-linking bond cannot be continuously formed, the script increases the cross-linking bonding distance threshold and continues to perform the loop operation until the target cross-linking degree is reached. The bonding distance threshold is between the solvent bead radius and the cutoff radius. In addition, the cross-linking bonding distance threshold is increased and the loop calculation is continued after the same bonding distance threshold is increased three times in each simulation cycle.

[0029] Compared with the prior art, the present application has the following advantages and beneficial effects:

[0030] 1. The present application provides an automatic simulation method for dissipative particle dynamics research on the cross-linking process of self-assembly of cross-linked polymer nanomaterials. The method can be used to explore the cross-linking process of all polymer nanomaterials (micelles, hydrogels, liposomes, etc.). The method first makes the polymer self-assemble to form aggregates, and then replaces the cross-linking agent molecules randomly, which can effectively maintain the invariability of the DPD simulation density. In addition, the method also fully considers the self-assembly characteristics of the polymer, the spatial steric hindrance restriction existing in the cross-linking process after the formation of the polymer aggregate, and the characteristics of the cross-linking agent itself. At present, there is no coarse-grained simulation method for the cross-linking of the cross-linked polymer nanomaterials.

[0031] 2. The present application can explain the micro-kinetic behavior of the cross-linking process of the cross-linked polymer nanomaterials from a micro perspective. Therefore, the simulation degree of the method of the present application is more consistent with the experiment, and the method can be used to explore the influence of the cross-linking strategy on the structural stability of the cross-linked polymer nanomaterials in the cross-linking process. At the same time, the method can also be applied to cross-linked polymer nanomaterials with multiple cross-linking sites, and further explore the influence of different types of cross-linking agents on the self-assembly cross-linking process of the cross-linked polymer nanomaterials.

[0032] 3. The method of the present application is fast and easy to implement, and the calculation result is accurate and consistent with the experimental result. The method can make up for the deficiency of experimental means, efficiently simulate the cross-linking process of the cross-linked polymer nanomaterials from a micro perspective, accurately explain the micro-kinetic behavior of the cross-linking process of the cross-linked polymer nanomaterials, and explore the influence of the cross-linking strategy on the structural stability of the cross-linked polymer nanomaterials, thereby providing theoretical guidance for the design and structure controllable construction of the cross-linked polymer nanomaterials in the experiment. BRIEF DESCRIPTION OF DRAWINGS

[0033] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the embodiments will be briefly introduced. Obviously, the drawings in the following description only constitute some embodiments of the present application, and for those skilled in the art, other drawings can be obtained based on these drawings without any creative effort.

[0034] Figure 1 The flow chart of the automatic simulation method of the self-assembly and cross-linking process of the high-molecular nanomaterial based on the coarse-grained simulation technology according to the embodiment of the present application;

[0035] Figure 2 The morphology change graph of the self-assembly, cross-linking agent replacement and cross-linking process of the cross-linked high-molecular nanomaterial according to the embodiment of the present application;

[0036] Figure 3 The topological structure parameterization formula derivation graph of the coarse-grained model of the cross-linking agent molecule according to the embodiment of the present application;

[0037] Figure 4 (A) is a detail graph of the coarse-grained mapping of the high-molecular system according to the embodiment of the present application;

[0038] Figure 4 (B) is a coarse-grained model graph of the high-molecular with topological structure and the cross-linking agent molecule according to the embodiment of the present application;

[0039] Figure 5 (A) is a morphology change graph of the micelle self-assembly, cross-linking agent replacement and cross-linking process of the cross-linked high-molecular nanomaterial according to the embodiment of the present application;

[0040] Figure 5 (B) is an end-to-end probability distribution graph of the cross-linking agent which has been cross-linked or not cross-linked according to the embodiment of the present application;

[0041] Figure 5 (C) is a cross-linking degree change trend graph of the cross-linking process of the high-molecular cross-linked micelle according to the embodiment of the present application;

[0042] Figure 5 (D) is a morphology comparison graph of the high-molecular cross-linked micelle before and after the cross-linking reaction according to the embodiment of the present application;

[0043] Figure 6 (A) is a morphology graph of the change of the micro-kinetic behavior of the cross-linking process of the high-molecular cross-linked micelle according to the embodiment of the present application;

[0044] Figure 6 (B) is a schematic graph of the influence of the cross-linking strategy on the structural stability of the high-molecular cross-linked micelle according to the embodiment of the present application;

[0045] Figure 7 (A) is a DPD self-assembly cross-linked micelle morphology graph of the coarse-grained model of the high-molecular with topological structure and different block ratios according to the embodiment of the present application;

[0046] Figure 7 (B) is a schematic diagram for stability evaluation of the embodiment of the present application;

[0047] Figure 7 (C) is a graph of experimental data results of the embodiment of the present application. DETAILED DESCRIPTION

[0048] In order for those skilled in the art to better understand the scheme of the present application, the technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0049] In the present application, the phrase "embodiment" means that the specific features, structures or characteristics described in combination with the embodiment can be contained in at least one embodiment of the present application. The appearance of this phrase at various places in the specification does not necessarily mean the same embodiment, nor is it an independent or alternative embodiment to other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described in the present application can be combined with other embodiments.

[0050] Embodiment 1:

[0051] In this embodiment, a high molecular system represented by a typical methacrylate triblock polymer [PPMA x -b-POPMA y -b-PhGMA z ] and a crosslinking agent represented by a disulfide and pH dual-responsive small molecule (DTP) are selected.

[0052] Please refer to Figure 1 In one embodiment 1 of the present application, a high molecular nanomaterial self-assembly crosslinking process automation simulation method based on the coarse-grained simulation technology is provided, and the overall calculation process will be automatically executed by a Perl script, including the following steps:

[0053] S1, using the Mesocite module in the Materials Studio software, the pre-established high molecular mixed solution model is subjected to the first step DPD simulation to form a high molecular nanomaterial model, and the classification of solvent beads and the calculation of the amount of crosslinking agent according to the number of crosslinking sites and components in the high molecular material are realized by using a Perl script;

[0054] Further, the model box size is The size can effectively avoid the influence of periodic boundary structure; the elastic constant C, the integral step length Δt, the dissipation force parameter γ are 4.0, 0.05, 4.5 respectively, the step number of the first step DPD simulation is 150000; the self-assembly structure and the density distribution of the simulated polymer micelles are as shown in Figure 2 .

[0055] Further, the classification of the solvent beads records the coordinates of all solvent beads in the model and establishes a set Set1; the calculation of the amount of crosslinking agent used is calculated by recognizing the total number of crosslinking sites in the polymer material and inputting the target crosslinking degree.

[0056] S2, the coarse-grained mapping of the crosslinking agent molecule is realized by using the Materials Studio software and the Perl script, and the topological structure parameters are set up to establish the coarse-grained model of the crosslinking agent;

[0057] Further, the coarse-grained mapping of the crosslinking agent molecule is realized by using the Materials Studio software and the Perl script, and the topological structure parameters are set up to establish the coarse-grained model of the crosslinking agent; please refer to Figure 4 (B), specifically:

[0058] S21, the crosslinking agent molecule is mapped, and the obtained crosslinking agent coarse-grained beads are named in the form of A, B… according to the bonding sequence; please refer to Figure 4 (A);

[0059] S22, taking component A(a, b, c) as the starting point, the three-dimensional coordinate parameters of other components are parameterized according to the topological structure of the crosslinking agent, and the parameterization rule is: (a±r1cosα1±r2cosα2±…±r n cosα n ,b±r1sinα1±r2sinα2±…±r n sinα n ,c±r1sinβ1±r2sinβ2±…±r n sinβ n ), wherein r1, r2…r n is the bond length, α, α1…α n is the angle based on the x-axis, and β1…β n is the angle based on the xy plane, please refer to Figure 3 .

[0060] S3, randomly select the solvent beads classified in step S1, search for the adjacent solvent beads in the polymer nanomaterial model according to the coordinate of the topological structure parameter obtained in step S2, and replace the crosslinking agent molecules, and the crosslinking agent molecule replacement is executed in a loop until the target replacement amount is reached, and a high polymer nanomaterial-crosslinking agent mixed solution model is obtained through the second step DPD simulation;

[0061] Further, the step S3 is to replace the solvent beads in the polymer nanomaterial model with the crosslinking agent beads according to the coordinates of the topological structure parameters obtained in step S2. The replacement method is as follows: randomly select a solvent bead in Set 1, define the coordinates of the selected solvent bead as component A of the crosslinking agent, calculate the coordinates of the virtual points of the remaining components one by one according to the coordinates of the obtained topological structure parameters of the crosslinking agent, and screen the existence of solvent beads near the virtual points one by one by comparing the coordinates in Set 1. After all components are successfully screened and the corresponding space is searched for the nearest solvent beads and the corresponding coordinates of the solvent beads in Set 1, the virtual point position is added with the component solvent beads, and the crosslinking agent coarse-grained model is connected and counted. If any component does not screen a solvent bead in the search range, the replacement is cancelled, and the solvent bead is randomly selected again to execute the loop operation. When the loop ends and the number of crosslinking agents does not meet the standard, an error message "crosslinking agent cannot be added" is prompted, and the existing replaced crosslinking agent is output.

[0062] Further, after the process of replacing the solvent beads with the crosslinking agent beads is completed, the second step simulation is performed. The second step DPD simulation is 10000 steps to relax the structure, and the polymer nanomaterial-crosslinking agent mixed solution model is obtained. This can effectively reduce the unreasonable contact between solvent beads caused by the replacement of crosslinking agent molecules; please refer to Figure 5 (A).

[0063] S4, using Materials Studio software and Perl script to identify and classify the crosslinking sites of the polymer nanomaterial and the crosslinking agent in the polymer nanomaterial-crosslinking agent mixed solution model, and performing geometric optimization and third step DPD simulation to search for the coarse-grained bead pairs of the crosslinking sites meeting the bonding distance threshold value and add Harmonic constraint, and then continue to perform fourth step DPD simulation to analyze the virtual bond length of the crosslinking bead pairs and the end-to-end distance of the crosslinking agent to complete the crosslinking reaction process confirmation, and perform fifth step DPD simulation to obtain the structure of the optimized crosslinked polymer nanomaterial model; finally, through multiple cycles of the above geometric optimization, third step DPD simulation, fourth step DPD simulation, bonding analysis and fifth step DPD simulation until the target crosslinking degree is reached, the final crosslinked polymer nanomaterial model is obtained.

[0064] Further, the search method for the crosslinking sites of the polymer material and the crosslinking agent in step S4 is as follows:

[0065] The coarse-grained bead pairs of the crosslinking sites in the polymer material are uniformly set as R1, and the coarse-grained bead pairs of the crosslinking sites in the crosslinking agent coarse-grained model are uniformly set as R2. Meanwhile, multiple crosslinking agents are also supported, and the coarse-grained bead pairs of the crosslinking sites in the polymer material are uniformly set as R​3,5 , and the coarse-grained beads of the crosslinker molecule crosslinking site are uniformly named as R 4,6 ;

[0066] In which, the crosslinker coarse-grained model crosslinking site is identified and classified, and each crosslinker coarse-grained model is numbered and classified into the uncrosslinked crosslinker set Set2.

[0067] Further, the step S4 is further subjected to geometric optimization and third step DPD simulation, searching for crosslinking site bead pairs that meet the bonding distance threshold, specifically:

[0068] The number of steps of the third step DPD simulation is 2000; for a single crosslinker system, the distances of all R1 bead pairs and R2 bead pairs are calculated, the bead pairs with a distance less than the bonding distance threshold are marked and classified into the pseudo-crosslinking bead pair set Set3 for subsequent calculation; at the same time, the crosslinker coarse-grained model involved is classified into the pseudo-crosslinking crosslinker set Set4 and removed from Set2; for a multi-crosslinker system, the calculation, screening and classification into the corresponding set are completed one by one according to the method of the single crosslinker system for subsequent calculation.

[0069] The harmonic constraint is realized by an elastic coefficient k, which is set to 0.032.

[0070] Specifically, the step S4 continues to perform the fourth step DPD simulation to analyze the virtual bond length of the pseudo-crosslinking bead pair and the end-to-end distance of the crosslinker to complete the crosslinking reaction process confirmation, wherein the end-to-end distance probability distribution diagram of the crosslinker is as shown in Figure 5 (B); specifically:

[0071] The number of steps of the fourth step DPD simulation is 15000; the analysis of the virtual bond length of the pseudo-crosslinking bead pair is to analyze whether the virtual bond length of the pseudo-crosslinking bead pair in Set3 before and after the fourth step DPD simulation is less than the cutoff radius, to judge whether the pseudo-crosslinking bond is stable, and then to determine the bonding situation; the bead pairs that do not meet the conditions are removed from Set3, and the corresponding crosslinker coarse-grained model is removed from Set4 and added to Set2 again;

[0072] The calculation of the end-to-end distance of the crosslinker is to calculate the end-to-end distance of the crosslinker coarse-grained model in Set2 and Set4 respectively, to judge the rationality of the crosslinking process, and the two groups of end-to-end distances are not more than 0.1 nm.

[0073] The step S4 is realized by the fifth step DPD simulation, and the simulation step number is 5000.

[0074] The step S4 is repeated until the target crosslinking degree is reached by the above-mentioned geometric optimization, the third step DPD simulation, the fourth step DPD simulation, the bond analysis and the fifth step DPD simulation. If the crosslinking bond cannot be continuously formed under the condition of a specified bond distance threshold, the script increases the crosslinking bond distance threshold and continues to execute the loop operation until the target crosslinking degree is reached. In addition, when the crosslinking degree does not meet the requirement after reaching the set bond distance threshold, an error "crosslinking reaction cannot continue to occur" is prompted, and the existing crosslinking degree and the corresponding crosslinking polymer nanomaterial model are output. The bond distance threshold is between the solvent bead radius and the cutoff radius. In addition, the crosslinking bond distance threshold is increased and the loop calculation is continued after the same bond distance threshold is simulated for three times in each round. The crosslinking degree change trend of the polymer crosslinking micelles in the crosslinking process is shown in Figure 5 (C); after the completion of the crosslinking process, the corresponding crosslinking polymer nanomaterial model is output; please refer to Figure 5 (D) for the comparison of the micelle morphology before and after the crosslinking reaction of the polymer crosslinking micelles.

[0075] In this example, the polymer nanomaterial self-assembly crosslinking process automation simulation method based on the coarse-grained simulation technology is successfully applied to the study of the microkinetic behavior of the polymer crosslinking micelle crosslinking process, as shown in Figure 6 Figure 6 (A) is a micelle morphology change graph under different crosslinking degrees, and Figure 6 (B) is a micelle density distribution graph under different crosslinking degrees.

[0076] The bond formation process of the crosslinking reaction of the polymer nanomaterial is first verified by the DPD simulation after the fitting of the restriction potential, and the crosslinking bond is formed. The kinetic behavior is more reasonable and the simulation degree is higher. At the same time, the test of the crosslinking agent properties further ensures the rationality of the reaction process. Therefore, the method of the present application can accurately reflect the microkinetic behavior of the crosslinking process of the polymer nanomaterial.

[0077] The original steric hindrance and special topological structure of the polymer self-assembly aggregate greatly affect the kinetic behavior of the crosslinking process, and the topological structure of the crosslinking agent also affects the above-mentioned process. The method of the present application first obtains the model of the polymer nanomaterial, and then replaces the coarse-grained model of the crosslinking agent with topological structure at the same density, which is most consistent with the experimental process.

[0078] Example 2

[0079] In order to verify the simulation degree of the crosslinking polymer nanomaterial self-assembly crosslinking process automation simulation method based on the coarse-grained simulation technology on the experimental system, nine kinds of polymer crosslinking micelle DPD models with different block ratios [PPMA x -b-POPMA y -b-PhGMA​z ],like Figure 7 (A), the kinetic and thermodynamic stabilities of different cross-linked micelles were further characterized, e.g. Figure 7 (B) shown.

[0080] The results showed that the polymer hOP8[PPMA6-b-POPMA 10 -b-PhGMA 14 ] have excellent kinetic and thermodynamic stability. The polymer hOP2 has good kinetic stability, while the polymer hOP7 has good thermodynamic stability. The corresponding polymers were prepared by ATRP polymerization. Experiments showed that hOP8 showed excellent anti-protein stability. Thanks to its good thermodynamic / kinetic stability, hOP7 / hOP2 also showed good anti-protein stability. Figure 7 Therefore, the automated simulation method of the cross-linking process of cross-linked polymer nanomaterials self-assembly based on coarse-grained simulation technology is very important for exploring the influence of cross-linking strategies on the structural stability of polymer nanomaterials, which greatly improves the simulation accuracy of coarse-grained simulation.

[0081] It should be noted that, for the sake of convenience, the aforementioned method embodiments are all expressed as a series of action combinations, but those skilled in the art should know that the present invention is not limited to the described order of actions, because according to the present invention, certain steps can be performed in other orders or simultaneously.

[0082] Those skilled in the art can understand that all or part of the processes in the above-mentioned embodiment methods can be completed by a computer program instructing relevant hardware. The program can be stored in a non-volatile computer readable storage medium, and when executed, can include the processes of the above-mentioned embodiment methods. Any reference to memory, storage, database or other medium used in the embodiments provided by the present application can include non-volatile and / or volatile memory. Non-volatile memory can include read-only memory (ROM), programmable ROM (PROM), electrically programmable ROM (EPROM), electrically erasable programmable ROM (EEPROM) or flash memory. Volatile memory can include random access memory (RAM) or external cache memory. As an illustration but not limitation, RAM is available in various forms, such as static RAM (SRAM), dynamic RAM (DRAM), synchronous DRAM (SDRAM), double data rate SDRAM (DDR SDRAM), enhanced SDRAM (ESDRAM), synchronous link (Synchlink) DRAM (SLDRAM), memory bus (Rambus) direct RAM (RDRAM), direct memory bus dynamic RAM (DRDRAM), and memory bus dynamic RAM (RDRAM), etc.

[0083] Any combination of the technical features of the above embodiments can be made. In order to make the description simple, all possible combinations of the technical features in the above embodiments are not described, however, as long as the combination of the technical features does not exist, it should be considered as the scope of the present application.

[0084] The above embodiments are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above embodiments, and any changes, modifications, substitutions, combinations and simplifications made without departing from the spirit and principles of the present application shall be equivalent replacement methods and shall be within the scope of protection of the present application.

Claims

1. An automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology, characterized in that: The steps include: S1. The pre-established polymer mixed solution model is subjected to the first step of DPD simulation of polymer self-assembly to obtain a polymer nanomaterial model; at the same time, the solvent beads of the polymer nanomaterial model are classified, and the amount of crosslinker used is calculated based on the number of crosslinking sites and components in the polymer material; S2, identifying the coarse-grained mapping and topological structure parameters of the cross-linker molecules to establish a coarse-grained model of the cross-linker; S3, randomly selecting the solvent beads classified in step S1, searching for adjacent solvent beads in the polymer nanomaterial model according to the coordinates of the topological structure parameters obtained in step S2 to replace the crosslinker molecules, repeating the crosslinker molecule replacement until the target replacement amount is reached, and performing the second step DPD simulation to obtain the polymer nanomaterial-crosslinker mixed solution model; S4. Identify and classify the cross-linking sites of the polymer material and the cross-linker in the polymer nanomaterial-cross-linker mixed solution model, and perform geometric optimization and the third-step DPD simulation, search for coarse-grained bead pairs of cross-linking sites that meet the bonding distance threshold and add harmonic constraints, continue to perform the fourth-step DPD simulation, analyze the virtual bond length of the simulated cross-linked bead pairs and the end-to-end distance of the cross-linker to complete the confirmation of the cross-linking reaction process, and perform the fifth-step DPD simulation to obtain the structure of the optimized cross-linked polymer nanomaterial model; finally, through multiple cycles of the above-mentioned geometric optimization, third-step DPD simulation, fourth-step DPD simulation, bonding analysis and fifth-step DPD simulation until the target cross-linking degree is reached, the final cross-linked polymer nanomaterial model is obtained.

2. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 1, characterized in that: The number of steps of the first DPD simulation in step S1 is 150,000; the solvent beads of the classified polymer nanomaterial model are to record the coordinates of all solvent beads in the model and establish a set Set1; the calculation of the cross-linking agent usage is obtained by identifying the total number of cross-linking sites in the polymer material and the input target cross-linking degree.

3. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 1, characterized in that: In step S2, the coarse-grained mapping and topological structure parameters of the cross-linker molecules are identified to establish a coarse-grained model of the cross-linker, specifically: S21, coarse-graining the cross-linker molecules, and naming the resulting cross-linker coarse-grained beads as components in the order of A, B, etc. according to the bonding sequence; S22. Taking component A (a, b, c) as the starting point, parameterize the three-dimensional coordinates of other components according to the cross-linker topology. The parameterization rules are: (a±r1cosα1±r2cosα2±…±r n cosα n ,b±r1sinα1±r2sinα2±…±r n sinα n ,c±r1sinβ1±r2sinβ2±…±r n sinβ n ) Among them, r1, r2…r n is the bond length; α, α1…α n is the angle between the y-axis and the x-axis; β1…β n The angle between the z-axis and the xy-plane.

4. The method for simulating the cross-linking process of self-assembly of polymer nanomaterials based on coarse-grained simulation technology according to claim 2, characterized in that: In step S3, the coordinates of the topological structure parameters obtained in step S2 are used to search for adjacent solvent beads in the polymer nanomaterial model to replace the crosslinker molecules. The replacement method is as follows: randomly select solvent beads in Set1, define the coordinates of the selected solvent beads as crosslinker component A, calculate the coordinates of the virtual points of the remaining components one by one according to the coordinates of the obtained crosslinker topological structure parameters, and screen the existence of solvent beads near the virtual points one by one by comparing the coordinates in Set1. After all components are successfully screened and the nearest solvent beads and the corresponding coordinates of the solvent beads in Set1 are searched in the corresponding space are deducted, the component solvent beads will be added to the virtual point position, and the coarse-grained model of the crosslinker molecule will be bonded and counted; if any component does not screen the solvent beads in the search range, the replacement is canceled, and the solvent beads are randomly selected again to perform a loop operation; after the process of replacing the crosslinker solvent beads with the solvent beads is completed, the second step DPD simulation is performed, and the number of steps of the second step DPD simulation is 10,000 steps to relax the structure and obtain a polymer nanomaterial-crosslinker mixed solution model; The virtual point only represents the coordinates, and the rule for screening the solvent beads near the virtual point is within the space.

5. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 1, characterized in that: The method for searching the cross-linking sites of the polymer material and the cross-linking agent in step S4 is: The coarse-grained bead pairs of cross-linking sites in polymer materials are uniformly named as R1, and the coarse-grained bead pairs of cross-linking sites in the cross-linker coarse-grained model are uniformly named as R2; at the same time, multi-cross-linking is also supported, in which case the coarse-grained bead pairs of cross-linking sites in polymer materials are uniformly named as R 3,5 , and the coarse-grained beads of the cross-linking sites of the cross-linker molecules are uniformly named as R 4,6 ; In addition to identifying and classifying the cross-linking sites of the cross-linker coarse-grained model, each cross-linker coarse-grained model needs to be numbered and classified into the uncross-linked cross-linker set Set2.

6. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 5, characterized in that: The geometric optimization and the third step DPD simulation in step S4 are performed to search for cross-linking site bead pairs that meet the bonding distance threshold. Specifically: The number of steps in the third step DPD simulation is 2000; for a single cross-linker system, the distances of all R1 bead pairs and R2 bead pairs are calculated, and the bead pairs with distances less than the bonding distance threshold are marked and classified into the pseudo-cross-linked bead pair set Set3 for subsequent calculations; at the same time, the coarse-grained models of the cross-linkers involved are classified into the pseudo-cross-linked cross-linker set Set4 and removed from Set2; for a multi-cross-linker system, the calculations, screening, and classification into the corresponding sets are completed one by one according to the method of a single cross-linker system for subsequent calculations.

7. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 1, characterized in that: The setting of the harmonic constraint in step S4 is achieved by the elastic coefficient k, which is set to 0.

032.

8. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 6, characterized in that: In step S4, the fourth step of DPD simulation is continued to analyze the virtual bond length of the simulated cross-linked bead pair and the end-to-end distance of the cross-linking agent to complete the confirmation of the cross-linking reaction process, specifically: The number of steps for executing the fourth step DPD simulation is 15,000. The virtual bond length of the pseudo-crosslinked bead pairs is analyzed by analyzing whether the virtual bond length of the pseudo-crosslinked bead pairs in Set3 is less than the cutoff radius before and after the fourth step DPD simulation, thereby determining whether the pseudo-crosslinked bond is stable and further determining the bonding situation. Bead pairs that do not meet the conditions are removed from Set3, and the corresponding crosslinker coarse-grained model is removed from Set4 and re-added to Set2. The calculation of the end-to-end distance of the crosslinker is to calculate the end-to-end distance of the coarse-grained model of the crosslinker in Set2 and Set4 respectively, to judge the rationality of the crosslinking process, and the end-to-end distance of the two groups does not exceed 0.1nm.

9. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 1, characterized in that: The step S4 is implemented through the fifth step DPD simulation, and the number of simulation steps is 5000.

10. The automated simulation method for the self-assembly and cross-linking process of polymer nanomaterials based on coarse-grained simulation technology according to claim 1, characterized in that: In step S4, the geometric optimization, the third-step DPD simulation, the fourth-step DPD simulation, the bonding analysis, and the fifth-step DPD simulation are repeated multiple times until the target cross-linking degree is reached. This means that if cross-links cannot continue to form under the specified bonding distance threshold, the script will increase the cross-linking bonding distance threshold and continue to perform the loop operation until the target cross-linking degree is reached; wherein the bonding distance threshold is between the solvent bead radius and the cutoff radius; in addition, after the same bonding distance threshold is repeated three times in each round of simulation, the cross-linking bonding distance threshold is increased and the loop calculation is continued.

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