CN108363901A - A kind of analogy method of pH response types block copolymer PAE-PEG loadings and release naphthalene molecule - Google Patents

Abstract

The invention discloses a kind of pH response types block copolymer PAE PEG to load the analogy method with release naphthalene molecule, it is the molecular model of method structure PAE PEG copolymers using Dissipative Particle Dynamics Simulation, naphthalene and water, to investigate under different pH environments PAE PEG copolymers to the loading and release behavior of naphthalene molecule.Then this method utilizes the methods of equilibrium configuration figure, radial distribution function to investigate influence of the pH value to PAE PEG polymer to naphthalene molecule loading and release behavior first by Materials Studio software building PEG PEA copolymer molecules, the mixed solution model of naphthalene molecule and hydrone.Analogy method of the present invention can explain that pH response type block copolymers load the behavioral mechanism with release naphthalene molecule from microcosmic angle, emulsified for efficient pH response types block copolymer PAE PEG and provide certain theoretical direction with the research being demulsified.

Description

Simulation of loading and releasing naphthalene molecules in a pH-responsive block copolymer PAE-PEG method

technical field

The invention relates to the research field of pH-responsive block copolymer emulsification and demulsification, in particular to a simulation method for pH-responsive block copolymer PAE-PEG loading and releasing naphthalene molecules.

Background technique

With the development of material science, the research and application of polymer materials are becoming more and more extensive. A copolymer composed of two or more polymers with different structures and properties is called a block copolymer. It can design the molecular weight, chemical structure and composition of the block copolymer according to the needs. Due to the thermodynamic incompatibility of different blocks of block copolymers, well-ordered core-shell micelles can be obtained by self-assembly in selective media. The dense hydrophobic inner core of this kind of micelles is used for the loading of hydrophobic substances, which can greatly improve the solubility of the carrier. The hydrophilic outer shell acts as a protective layer between the inner core and the solution, preventing the micelles from aggregating with each other, thus playing a stabilizing role, so that the micelles can obtain a longer cycle time under various environmental conditions. Polymeric micelles have the advantages of small particle size, large surface area/volume ratio, low critical micelle concentration (CMC) and large space for solubilization. Therefore, due to its excellent performance in solvents, the block copolymer can be used as an efficient hydrophobic delivery carrier tool, which is widely used in drug delivery systems, gene therapy, mineralization templates, and inducers for the synthesis of metal colloids. field.

The pH-responsive interlocking copolymer was obtained by modifying the structure of the amphiphilic copolymer by using pH-sensitive groups. Due to the different types of pH-sensitive groups, pH-responsive copolymers are mainly divided into two categories: weakly acidic polymers and weakly basic polymers. The typical characteristic of pH-responsive copolymers is that the polymer contains protonatable groups, and its important parameter is the pKa or pKb value. Weakly acidic polymers are protonated at pH below their pKa and deprotonated at pH above their pKa. The protonation/deprotonation changes of weakly basic polymers are the opposite. For example, the weakly acidic polymer polymethacrylic acid (Poly(methacrylic acid), PMAA) contains carboxyl groups, which accept protons at low pH to become hydrophobic-COOH, and donate protons at high pH to become hydrophilic The nature of -COO-; and weakly basic polymers such as polydiethylaminoethyl methacrylate (po (N, N-diethylaminoethyl methacrylate), PDEA) properties are just the opposite. Therefore, pH-responsive copolymers can realize the loading and controlled release of carriers according to changes in the acidic conditions of the environment. They are often used to load drug molecules to increase their targeting to cancer cells, improve drug delivery efficiency and reduce drug side effects. The tools of drug molecules are mostly used in the field of medicinal chemistry. At this stage, some researchers use experimental methods to study pH-responsive block copolymers loaded with hydrocarbon molecules to form oil-in-water emulsions, changing the pH value to protonate the pH groups of the copolymers to release hydrocarbon molecules, and to separate the oil-water phases . However, there are few reports on the theoretical research on the behavior mechanism of loading and releasing hydrocarbon molecules in pH-responsive block copolymers. Therefore, studying the behavioral mechanism of loading and releasing hydrocarbon molecules in pH-responsive block copolymers will provide a certain basis for in-depth exploration of the self-assembly behavior of pH-responsive block copolymers, the microstructural transformation of loading and releasing hydrocarbon molecules, and the carrier release mechanism. Guided by theory, the research field of pH-responsive copolymers has been extended from medicinal chemistry to oilfield chemistry.

Contents of the invention

The object of the present invention is to provide a simulation method for loading and releasing naphthalene molecules of a pH-responsive block copolymer PAE-PEG, which can explain the behavioral mechanism of pH-responsive block copolymer loading and releasing naphthalene molecules from a microscopic point of view, It provides some theoretical guidance for the research on the emulsification and demulsification of the highly efficient pH-responsive polymer PAE-PEG.

Its technical solutions include:

A kind of simulation method of copolymer PAE-PEG loading and releasing naphthalene molecule, comprises the following steps in sequence:

a to build the initial model,

Use the Bead Tpyes and Mesomolecule tools in the Materials Studio software to construct PAE-PEG copolymer molecules, naphthalene molecules, and water molecules, and change the ratio of -NH- and -NH ⁺ ₂ - in the PAE-PEG molecular chain to simulate different pH values , and perform force field distribution and preliminary optimization on each molecule;

Use the Mesostructrue tool to build a model box; randomly add the initially optimized copolymer molecules, naphthalene molecules, and water molecules into the model box to build a mixed solution model;

b Calculate the equilibrium configuration,

Using the Mesocite Tools module to optimize the dissipative particle dynamics of the mixed solution model described in step a, and then perform a dissipative particle dynamics simulation on the optimized model to obtain an equilibrium configuration;

cComprehensive analysis,

According to the trajectory file of the equilibrium configuration obtained in step b, analyze the equilibrium configuration diagram of the model; utilize the Analysis tool in the MesociteTools module to analyze the diameters of the copolymer hydrophobic segment poly-β amino ester, hydrophilic segment polyethylene glycol and naphthalene molecules The behavior of loading and releasing naphthalene molecules in the copolymer PAE-PEG was analyzed specifically by using the distribution function.

Compared with the prior art, the above-mentioned technical solution brings the following beneficial technical effects:

Using simulation methods to investigate the loading and release of naphthalene molecules by PAE-PEG copolymers does not need to consume a large amount of experimental materials and experimental equipment, which reduces costs, saves time, and has the advantages of high efficiency.

As a preferred solution of the present invention, the above-mentioned copolymer is a pH-responsive block copolymer.

Compared with the prior art, the present invention provides a simulation method for pH-responsive PAE-PEG copolymer loading and releasing naphthalene molecules, which is a method of dissipating particle dynamics to change the pH value of the solution to investigate different pH values Behavior of loading and releasing naphthalene molecules in PAE-PEG copolymer under ambient conditions. Firstly, the equilibrium configuration was calculated by building a mixed solution model, and then the effect of pH value on the loading and release behavior of PAE-PEG polymer on naphthalene molecules was investigated by using methods such as equilibrium configuration diagram and radial distribution function.

The simulation method of the present invention is fast in calculation, easy to implement, accurate in calculation results, and consistent with the experimental results; it can make up for the insufficiency of the experimental means, explain the mechanism of the interaction between the polymer and the surfactant from the microscopic point of view, and the HPAM-surfactant compound system The research on the properties of the gas-liquid interface provides some theoretical guidance.

Description of drawings

The present invention will be further described below in conjunction with accompanying drawing:

Fig. 1-Fig. 3 is poly-beta amino ester-polyethylene glycol, naphthalene, water molecule structural formula and coarse-grained bead division standard diagram;

Figure 4-Figure 7 is the initial configuration diagram of poly-β amino ester-polyethylene glycol molecule under different pH value environments;

Figure 8 is the initial configuration diagram of the mixed solution (PAE-PEG, naphthalene, H ₂ O) under different pH environments;

Fig. 9 is a radial distribution curve diagram of hydrophobic segment (PAE), hydrophilic segment (PEG) and naphthalene molecules in the equilibrium configuration of the mixed solution.

Detailed ways

The present invention proposes a simulation method for loading and releasing naphthalene molecules in a pH-responsive block copolymer PAE-PEG. In order to make the advantages and technical solutions of the present invention clearer and clearer, the present invention will be described in detail below in conjunction with specific examples.

The main chemicals used in the present invention, poly-beta amino ester-polyethylene glycol (PAE-PEG) and naphthalene, can be purchased through commercial channels.

Hereinafter, the present invention will be further described by taking the pH-responsive block copolymer as poly-β amino ester-polyethylene glycol PAE-PEG as an example.

Example 1:

A simulation method for pH-responsive PAE-PEG copolymer loading and releasing naphthalene molecules, specifically comprising the following steps:

Step 1, construct molecular structure,

According to the relevant experimental and theoretical literature of the pH-responsive copolymer poly-β amino ester-polyethylene glycol, the molecular structure formula of poly-β amino ester-polyethylene glycol, naphthalene, and water is obtained, and according to the hydrophilic and hydrophobic type of the molecular chain segment, the poly-β amino The structural formula of ester-polyethylene glycol, naphthalene, and water is divided into coarse-grained beads. The structural formula of poly-β amino ester-polyethylene glycol, naphthalene, and water and the division standards of coarse-grained beads are shown in Figure 1, Figure 2 and Figure 3. In 1, n=9, m=1, and the coarse-grained water molecule beads in Figure 3 contain 8 water molecules; secondly, according to the classification standard of coarse-grained beads, use the Bead Tpyes and Mesomolecule tools in the Materials Studio software to construct PAE-PEG copolymer molecules , naphthalene molecules, water molecules, change the ratio of -NH-(PAE) and -NH ₂ ⁺ -(PAEH) in the poly-β amino ester-polyethylene glycol molecular chain to simulate different pH values, and perform Force field distribution and initial optimization.

The initial configuration of the poly-β amino ester-polyethylene glycol molecule under different pH environments is shown in Figure 4 and Figure 5, wherein, in Figure 4, pH=7 (PAE:PAEH=5:0), and in Figure 5, pH=5.0 ( PAE:PAEH=0:5);

Step 2. Build the initial model,

Use the Mesostructrue Template module to construct the model box; secondly, use the Mesostructrue module to randomly add the optimized poly-β-urethane-polyethylene glycol molecules, naphthalene molecules, and water molecules into the model box according to the concentration ratio of 8%: 2%: 90%. Construct the initial configuration of the mixed solution, model box size Each coarse-grained bead has an average mass of 432 amu and a radius of The number density of beads in the box is ρ=3, and the truncation radius between coarse-grained beads is The initial configuration of the mixed solution (PAE-PEG, naphthalene, H ₂ O) in different pH environments is shown in Figure 6, and the copolymer PAE-PEG molecules, naphthalene molecules, and water molecules are randomly distributed in the model box;

Step 3, calculating the equilibrium configuration of the mixed solution,

Use the Mesocite Tools module to perform dissipative particle dynamics optimization (GeometryOptimization) on the mixed solution model, and then perform dissipative particle dynamics simulation (Dissipative ParticleDynamics) on the optimized model;

Mixed solution model dissipative particle dynamics optimization parameters: Compass is selected for force field, Atom Based method is used for Van der Waals interaction, Ewald method is used for Coulomb interaction, SmartMinimization is selected for optimization method, and the number of optimization steps is 5000 steps;

Mixed solution model dissipation particle dynamics simulation parameters: NVT ensemble is used to calculate molecular dynamics simulation, the temperature is selected as 298K, and the cut-off radius is selected The simulation time is 300000ps, the time step is 860fs, one frame is output every 1000 steps, the dissipation parameter (dissipation strength) is 4.5, the dissipation radius (dissipation radius) is 1.0, the mass scale (Mass scale) is 432amu, coarse-grained The parameters of the repulsive force between the beads are shown in Table 1;

Table 1

See Figure 7 and Figure 8 for the equilibrium configuration diagrams of mixed solutions under different pH environments. In Figure 7, pH=7 (PAE:PAEH=5:0), in Figure 8, pH=5.0 (PAE:PAEH=0:5) ; It can be seen from the figure that the naphthalene molecule is located inside the copolymer molecule, and the copolymer is loaded with naphthalene molecules; as the pH value decreases, the position of the copolymer molecule and the naphthalene molecule changes, and the copolymer releases the naphthalene molecule;

Step 4, comprehensive analysis,

According to the trajectory file of the equilibrium configuration of the mixed solution, use the Analysis tool in the Mesocite Tools module to analyze the radial distribution of the copolymer hydrophobic segment poly-β-amino ester (PAE), hydrophilic segment polyethylene glycol (PEG) and naphthalene molecules function, calculate the number of naphthalene molecules around the hydrophobic segment (PAE) and hydrophilic segment (PEG), and further analyze the influence of pH value on the loading and release behavior of PAE-PEG polymers on naphthalene molecules, as shown in Figure 9.

The parts not mentioned in the present invention can be realized by referring to the prior art.

On the basis of the above pH-responsive copolymer PAE-PEG, those skilled in the art can also use the method of the present invention to study the loading and releasing behavior of other pH-responsive copolymers.

It should be noted that any equivalent or obvious modification made by those skilled in the art under the teaching of this specification shall fall within the protection scope of the present invention.

Claims (2)

1. a kind of simulation method of copolymer PAE-PEG loading and releasing naphthalene molecule, is characterized in that, comprises the following steps successively: a to build the initial model, Use the Bead Tpyes and Mesomolecule tools in the Materials Studio software to construct PAE-PEG copolymer molecules, naphthalene molecules, and water molecules, and change the ratio of -NH- and -NH ⁺ ₂ - in the PAE-PEG molecular chain to simulate different pH values , and perform force field distribution and preliminary optimization on each molecule; Use the Mesostructrue tool to build a model box; randomly add the initially optimized copolymer molecules, naphthalene molecules, and water molecules into the model box to build a mixed solution model; b Calculate the equilibrium configuration, Using the Mesocite Tools module to optimize the dissipative particle dynamics of the mixed solution model described in step a, and then perform a dissipative particle dynamics simulation on the optimized model to obtain an equilibrium configuration; cComprehensive analysis, According to the trajectory file of the equilibrium configuration obtained in step b, analyze the model equilibrium configuration diagram; utilize the Analysis tool in the Mesocite Tools module to analyze the poly-β amino ester of the copolymer hydrophobic segment, the polyethylene glycol of the hydrophilic segment and the naphthalene molecule The radial distribution function was developed to analyze the behavior of loading and releasing naphthalene molecules in the copolymer PAE-PEG. 2. A method for simulating the loading and release of naphthalene molecules by copolymer PAE-PEG according to claim 1, characterized in that: said copolymer is a pH-responsive block copolymer.