CN115116566A

CN115116566A - Method and system for screening intraocular lens material

Info

Publication number: CN115116566A
Application number: CN202210056854.6A
Authority: CN
Inventors: 吴明星; 毛雁; 刘良平
Original assignee: Zhongshan Ophthalmic Center
Current assignee: Zhongshan Ophthalmic Center
Priority date: 2022-01-18
Filing date: 2022-01-18
Publication date: 2022-09-27
Anticipated expiration: 2042-01-18
Also published as: CN115116566B

Abstract

The application belongs to the technical field of intraocular lens materials, and particularly relates to a method and a system for screening intraocular lens materials. The screening method of the present application comprises: obtaining the molecular structural formula of a monomer and a cross-linking agent in the intraocular lens material to be screened and the dosage ratio of the monomer to the cross-linking agent; constructing an artificial lens model by utilizing the molecular structural formula and the dosage ratio; performing molecular dynamics simulation on the artificial lens model to obtain the overall structural characteristics of the model; and then obtaining a representative structure through cluster analysis, wherein the representative structure is used for simulating and testing the performance of the subsequent artificial lens model material, the representative structure comprises a refractive index, a glass transition temperature, a stress-strain curve and a solvent accessible area, and the artificial lens material meeting the preset requirement is screened from the artificial lens material to be screened according to the parameters. The screening method of the present application optimizes the composition of the intraocular lens material and screens a more optimal composition of the intraocular lens material for practical production applications.

Description

Method and system for screening intraocular lens material

Technical Field

The application belongs to the technical field of intraocular lens materials, and particularly relates to a method and a system for screening intraocular lens materials.

Background

On a global scale, cataracts are the second leading cause of blindness, now in addition to age-related macular degeneration. It is estimated that there are about 2000 million cataract surgeries worldwide each year, and as the mean life span increases, there is a growing increase in cataract patients. In China, cataract is still the first eye disease causing blindness. Currently, optical replacement of intraocular lenses is the first method of treatment for cataracts.

Intraocular lens optic materials have continued to improve and develop. The first intraocular lens invented by Harold Ridley Jazz, 1949, was made of Polymethylmethacrylate (PMMA), which was chosen because of its high transparency and good biocompatibility, but it was not foldable and required implantation through a large incision, increasing postoperative risks and hospital stay. With the continual improvement of intraocular lens design and surgical techniques, Charles Kelman in the 70's of the 20 th century invented phacoemulsification, reducing the surgical incision and the development of diversified intraocular lens materials. Today, phacoemulsification combined with folded intraocular lens implantation is the primary surgical approach for cataract treatment, and since intraocular lenses need to be implanted through small incisions, there are many types of intraocular lenses, both in terms of their optical properties and in terms of the material itself. Materials currently applied to intraocular lenses in the market are mainly classified into two major categories, the first category being the aforementioned hard materials (PMMA materials), and the second category being foldable materials including silicone gel, hydrogel, hydrophilic and hydrophobic acrylates, and the like. The main component of the silicone gel is methyl vinyl siloxane and a derivative polymer thereof, the silicone gel has good optical characteristics and stable chemical structure, is a first-generation foldable material, but has low refractive index, and the artificial lens of the silicone gel is slightly thicker than other artificial lenses at the same refractive power and is easy to generate electrostatic reaction and adhere cells, bacteria and the like. The hydrophilic acrylate material has good compatibility with grape membranes, and light postoperative inflammation and exudation reaction, but metabolites and pollutants are easy to remain to cause intraocular lens opacity. The hydrophobic acrylate material has high refractive index, is light and thin, is more suitable for being implanted through a small incision, and has high surface viscosity, so that the incidence rate of posterior capsular opacification and proliferation of lens epithelial cells is extremely low. At present, the hydrophobic polyacrylate type artificial lens becomes the first choice of most ophthalmologists, but the surface light scattering phenomenon is found to occur clinically, and the postoperative visual quality of a patient is affected.

The phenomenon of glaring is caused by that the refraction index of vacuole formed by hydration in the artificial lens material is different from that of the surrounding body material, so that light is refracted and scattered at the interface of liquid and polymer. The phenomenon of glistening, observed by optical microscopy, is generally distributed over the optic zone of the lens, and these vacuoles are predominantly spherical and ellipsoidal in shape, varying in size from a few microns to tens of microns, depending on the particular lens material and temperature. The phenomenon of glistening is most commonly found in hydrophobic acrylic intraocular lenses, but different hydrophobic acrylic intraocular lenses have different abilities to eliminate or reduce glistening. At present, the main trend of hydrophobic acrylic intraocular lens manufacturers is to make the materials less shiny, although there have been many experiments to develop new non-glittering hydrophobic acrylic intraocular lenses (US 5.693.095, US 6.140.438, US 6.326.448), most manufacturers do not disclose their exact material composition.

The ideal intraocular lens material needs to have the following characteristics: (1) the optical performance is good, the refractive index is high, the light transmittance is high, and the visual requirement of a patient is met; (2) the physical and chemical properties are stable, and the mechanical traction can be resisted; (3) the grape film and the capsule film have good biocompatibility; (4) easy to implant and take out, and easy to sterilize and process. Hydrophobic acrylic acid as an artificial lens material is generally prepared by initiating polymerization of two or more monomers and a cross-linking agent under the action of an initiator to obtain a cross-linked network structure. Different monomer and cross-linking agent selections have great influence on the synthesis of the copolymer, so that the physical and chemical properties of the synthetic material are different, and different optical properties, mechanical properties and biocompatibility are caused. The irregular polymer network structure is considered to be one of the most complex molecular structures. Neither industrially nor in the laboratory prepared crosslinked polymer products can their topology be obtained experimentally. The polymer network structure is closely related to its properties. The traditional artificial lens material is preferably synthesized and processed in a laboratory by selecting different synthesis methods (casting and cutting) according to the characteristics of different monomers, and finally, the characteristics of the synthesized artificial lens are evaluated by a laboratory characterization method. In order to obtain a relatively ideal sparkless intraocular lens material, the core part of the model structure for constructing the accurate intraocular lens material is the model structure.

In summary, intraocular lens materials, as an irregular polymer network structure, are considered to be one of the most complex molecular structures. The polymer network structure is closely related to its properties, but neither of their topologies can be obtained experimentally. The prior artificial lens optimization method needs to be carried out in a laboratory, needs to consume a large amount of labor and material cost, and has certain limitations. Therefore, how to provide a design method of an intraocular lens material, which provides a solid theoretical basis and guidance for obtaining an ideal sparkless intraocular lens material, is a technical problem to be solved urgently.

Disclosure of Invention

In view of the above, the present application provides a method and system for screening intraocular lens materials, which optimizes the structural (monomer and cross-linker selection) composition of the intraocular lens materials, and screens more optimal intraocular lens material compositions for practical production applications.

In a first aspect, the present application provides a method for screening intraocular lens material, comprising:

obtaining the molecular structural formula of a monomer and a cross-linking agent in the intraocular lens material to be screened and the dosage ratio of the monomer to the cross-linking agent;

constructing an artificial lens model by using the molecular structural formula and the dosage ratio, and optimizing the artificial lens model;

performing molecular dynamics simulation on the optimized artificial lens model by using a molecular dynamics method to obtain an RMSD value of the overall structural characteristic of the artificial lens model;

according to the track file obtained by the molecular simulation, carrying out clustering analysis on the artificial lens model to obtain an artificial lens model with a representative structure;

calculating the refractive index, glass transition temperature, elongation and intraocular lens solvent accessible area of the representative structural intraocular lens model;

and screening the intraocular lens material meeting the preset requirement from the intraocular lens materials to be screened according to the RMSD value, the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens.

Specifically, the artificial lens model can be constructed by adopting the conventional full-atom model construction software; and performing molecular dynamics simulation on the artificial lens model by adopting the conventional molecular dynamics simulation software, wherein the conventional molecular dynamics simulation software is used for performing geometric configuration optimization on the artificial lens model by combining the experiment temperature and the experiment environment of the artificial lens.

In another embodiment, the method for screening intraocular lens materials meeting preset requirements from the intraocular lens materials to be screened according to the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens specifically comprises the following steps:

and taking the intraocular lens material to be screened, of which the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens all accord with corresponding preset ranges, as the intraocular lens material which accords with preset requirements.

Specifically, the overall structural characteristic RMSD value of the artificial lens model can be simulated by the conventional molecular dynamics of 500ns to obtain RMSD results.

Specifically, the glass transition temperature and refractive index of the representative structural intraocular lens model described herein: the glass transition temperature is an inherent property of amorphous polymeric materials and can be obtained by molecular dynamics simulation under NPT conditions. By simulation and testing of the representative structural intraocular lens model, the change in specific volume with temperature can be obtained, and thus the value of the glass transition temperature can be derived from the slope of the change.

In another embodiment, constructing the intraocular lens model specifically comprises:

constructing an intraocular lens model by using the molecular structural formula and the dosage ratio under AMBER20 software tLeap module and Gaussian16 software;

the optimization of the intraocular lens model specifically comprises:

performing geometric optimization by using a density functional theory and a Gaussian16 B.01 program, and applying a B3LYP functional, 6-31G (d) group to all atoms; the optimized structure of polymer chains was then filled into the intraocular lens model using PackMOL software.

Specifically, constructing the intraocular lens model and optimizing the model comprises:

construction: and (3) building a full-atom model structure of the intraocular lens material with the help of AMBER20 software tLeap module and Gaussian16 software according to the content of the cross-linking agent and the monomer in a certain proportion.

Optimizing: geometric optimization was performed using the density functional theory and the Gaussian16 B.01 program, using the B3LYP functional, with the 6-31G (d) basis set being applied to all atoms. The optimized structure of polymer chains was packed into an intraocular lens model, selected as the starting point for subsequent molecular dynamics simulations, using PackMOL software.

In another embodiment, the performing molecular dynamics simulation on the optimized intraocular lens model specifically includes:

and (3) carrying out molecular dynamics simulation on the artificial lens model through an AMBER universal force field of organic molecules to obtain a molecular dynamics model.

Specifically, the molecular dynamics simulation of the optimized intraocular lens model specifically comprises:

for all intraocular lens models, the AMBER universal force field (version 2.11, 2016. 5. month) (GAFF2) of organic molecules was used for Molecular Dynamics (MD) simulations. All MD simulations of the intraocular lens model were performed with the AMBER20 software package. The topology files necessary for the MD simulation are made by AMBER20 softwareThe Antechamp module is prepared. The model of the intraocular lens system was separately solvated in an octahedral periodic box with a TIP3P water model. The particular between the outermost intraocular lens atoms and the simulated box wall is selected

A distance. The molecular dynamics simulation of the intraocular lens system was performed using the following simulation strategy.

The method specifically comprises the following steps:

the first step is as follows: based on the model obtained by the PackMOL software, energy minimization was performed to obtain a lower energy starting conformation of the intraocular lens model for subsequent MD simulation. 8000-step steepest descent and 12000-step conjugate gradient minimization were performed, i.e. 20000 steps were performed in total per iol model.

The second step is that: the structure resulting from the minimization is further optimized using a two-stage equilibrium simulation. In the first phase of the equilibrium simulation, the intraocular lens model was simulated for 100ns at a temperature of 500K under NPT conditions. In the second phase of the equilibrium simulation, the intraocular lens model system was subjected to a slow cooling simulation procedure under NPT conditions for 100 ns. The models were cooled from 500K to 220K at 1 atmosphere with 20K intervals. Therefore, the cooling rate used in the equilibrium simulation was 2.8X 109-1.

The third step: the artificial lens model system finally simulates 500ns under the NPT with periodic boundary conditions, and the obtained RMSD result is the overall structural characteristics of the model.

In another embodiment, the method for calculating the refractive index value includes: calculating the system polarizability value of the representative structure intraocular lens model under an electric field with preset intensity applied in the xyz direction by using Gaussian16 software, and obtaining the refractive index of the molecular dynamics model through the analysis and calculation of Mulfiwfn software.

In another embodiment, the method of calculating the elongation comprises:

limiting coordinates of the representative structural intraocular lens model;

then opening the limit to optimize the artificial lens model with the representative structure and solvent molecules in the system;

heating the representative structural intraocular lens model to 600K to relax the structure of the representative structural intraocular lens model at a high temperature, and slowly cooling the representative structural intraocular lens model from 600K to 240K over a simulation time of 50 ns;

balancing at the temperature of 310K, generating a stress-strain curve of the artificial lens model with the representative structure by uniaxial compression simulation, and collecting data to calculate the stress-strain curve;

calculating the elongation of the representative structural intraocular lens model using the stress-strain curve.

At present, the hydrophobic polyacrylate intraocular lens becomes the first choice of most ophthalmologists, but the situation that part of the intraocular lens generates the phenomenon of glaring clinically and the visual quality of a patient is influenced is found.

In another embodiment, the method for calculating the solvent accessible area of the intraocular lens comprises:

heating the representative structural intraocular lens model to 400K at a simulated temperature of 300K in 50ns, and then cooling to 300K in 50 ns;

the solvent accessible area of the intraocular lens of the cooled representative structural intraocular lens model was calculated.

In another embodiment, the preset range corresponding to the refractive index is greater than or equal to 1.50; the preset range corresponding to the glass transition temperature is 253.15K-298.15K; the preset range corresponding to the elongation is more than or equal to 150 percent; the solvent accessible area of the artificial lens is not more than the corresponding preset range

In particular, the refractive index, the glass transition temperature, the stress-strain analysis and the characterization of the solvent accessible area of the intraocular lens in the present application specifically include:

performing cluster analysis on the intraocular lens model, and obtaining an intraocular lens model of each representative structure through the cluster analysis for simulation and test of material performance of a subsequent intraocular lens model, wherein the cluster analysis comprises the following steps: refractive index, glass transition temperature, stress strain analysis, and solvent accessible area.

In a second aspect, the present application provides a system for screening intraocular lens material comprising:

the device comprises an acquisition unit, a first modeling unit, an optimization unit, a second modeling unit, an analysis unit, a calculation unit and a screening unit;

the obtaining unit is specifically configured to: obtaining the molecular structural formula of a monomer and a cross-linking agent in the intraocular lens material to be screened and the dosage ratio of the monomer to the cross-linking agent;

the first modeling unit is specifically configured to: constructing an artificial lens model by utilizing the molecular structural formula and the dosage ratio;

the optimization unit is specifically configured to: optimizing the intraocular lens model;

the second modeling unit is specifically configured to: performing molecular dynamics simulation on the optimized artificial lens model by using a molecular dynamics method to obtain an RMSD value of the overall structural characteristics of the artificial lens model;

the analysis unit is specifically configured to: performing cluster analysis on the artificial lens model according to the overall structure characteristic RMSD value to obtain an artificial lens model with a representative structure;

the computing unit is specifically configured to: calculating the refractive index, glass transition temperature, elongation and intraocular lens solvent accessible area of the representative structural intraocular lens model;

the screening unit is specifically configured to: and screening the intraocular lens materials meeting the preset requirements from the intraocular lens materials to be screened according to the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens. .

In another embodiment, the screening unit specifically includes: and taking the intraocular lens material to be screened, of which the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens all accord with corresponding preset ranges, as the intraocular lens material which accords with preset requirements.

In order to obtain a relatively ideal intraocular lens material, the application aims to provide a novel intraocular lens material screening and designing method, the whole process is to construct an intraocular lens model, optimize the model, perform molecular dynamics simulation on the optimized model to obtain an RMSD value, namely the overall structural characteristic of the intraocular lens model, then obtain a representative structure through cluster analysis, use the representative structure for subsequent simulation and test (refractive index, glass transition temperature, stress-strain curve, solvent accessible area) of the intraocular lens model material performance, and finally screen according to all values, and a design scheme is provided for obtaining a new and preferred intraocular lens material through the method. According to the method, a molecular dynamics model composed of different monomers and cross-linking agents is established on the basis of a constructed artificial lens model based on molecular dynamics simulation, and the characterization parameters of the different models are calculated through the molecular dynamics model so as to evaluate the polymerization effect of the different combined monomers and the cross-linking agents. The better scheme for synthesizing the subsequent intraocular lens material is obtained by screening, so that the cost is reduced, and the production efficiency is improved.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.

FIG. 1 is a full atomic model structure of an intraocular lens provided in example 1 of the present application;

FIG. 2 is a full atomic model structure of an intraocular lens provided in example 2 of the present application;

FIG. 3 is a full atomic model structure of an intraocular lens provided in example 3 of the present application;

FIG. 4 is a stress-strain curve of the model of examples 1-3 provided in example 5 of the present application, subjected to molecular dynamics simulation;

FIG. 5 shows the RMSD results of molecular dynamics simulations performed on the models of examples 1 to 3 provided in example 7 of the present application;

fig. 6 is a graph showing the actual flare-formation induced in vitro by acryssofsn 60WF iol, SensarAR40e iol, and envistam 60 iol provided in example 6 of the present application.

Detailed Description

The application provides a method and a system for screening intraocular lens materials, which are used for solving the technical defects of time and labor waste in selection and design of intraocular lens materials in the prior art.

The technical solutions in the embodiments of the present application will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments in the present application without making any creative effort belong to the protection scope of the present application.

Wherein, the raw materials or reagents used in the following examples are all commercially available or self-made.

Polymethyl methacrylate (PMMA), phenylethyl acrylate (PEA), phenylethyl methacrylate (PEMA), butanediol diacrylate (BDDA), Ethyl Acrylate (EA), Ethyl Methacrylate (EMA), 2,2, 2-trifluoroethyl methacrylate (TFEMA), ethylene glycol dimethacrylate (EG-DMA), polyethylene glycol phenyl ether acrylate (PEG-PEA), 2-hydroxyethyl methacrylate (HEMA), Styrene (Styrene) of the following examples.

The following examples demonstrate the screening method for intraocular lens material:

the feasibility of the screening method of the application is verified by the known monomers and cross-linking agents of the artificial lens and the proportional relation parameters, and comprises the following steps:

(1) constructing an artificial lens model, namely a full-atom model of the artificial lens model, and optimizing the artificial lens model:

1) according to the known content ratio of the cross-linking agent and the monomer of the intraocular lens, a full-atom model structure of the intraocular lens material is built under the assistance of AMBER20 software tLeap module and Gaussian16 software.

2) Optimizing: geometric optimization was performed using the density functional theory and the Gaussian16 B.01 program, using the B3LYP functional, with the 6-31G (d) basis set being applied to all atoms. The optimized structure of the polymer chains was packed into an intraocular lens model, selected as the starting point for subsequent molecular dynamics simulations, using PackMOL software.

(2) Performing molecular dynamics simulation on the optimized artificial lens model, wherein the molecular dynamics simulation comprises the following steps: and (3) performing molecular dynamics simulation on the optimized artificial lens model by using a molecular dynamics method to obtain an RMSD value of the overall structural characteristics of the artificial lens model.

The specific method comprises the following steps: for all intraocular lens models, the AMBER universal force field (version 2.11, 2016 month 5) (GAFF2) of organic molecules was used for Molecular Dynamics (MD) simulations. All MD simulations of the intraocular lens were performed with the AMBER20 software package. The topology file necessary for MD simulation is prepared by the Antechamber module of the AMBER20 software. The model of the intraocular lens system was separately solvated in an octahedral periodic box with a TIP3P water model. Features between the outermost intraocular lens atom and the simulated box wall are selectedStator

Distance. The molecular dynamics simulation of the intraocular lens system was performed using the following simulation strategy.

The first step is as follows: based on the model obtained by the PackMOL software, energy minimization was performed to obtain a lower energy starting conformation of the intraocular lens model for subsequent MD simulation. 8000 steps of steepest descent and 12000 steps of conjugate gradient minimization were performed, i.e. a total of 20000 steps of minimization were performed per intraocular lens model.

The second step: the structure resulting from the minimization is further optimized using a two-stage equilibrium simulation. In the first phase of the equilibrium simulation, the intraocular lens model was simulated for 100ns at a temperature of 500K under NPT conditions. In the second phase of the equilibrium simulation, the intraocular lens model system was subjected to a slow cooling simulation procedure under NPT conditions for 100 ns. The models were cooled from 500K to 220K at 1 atmosphere with 20K intervals. Thus, the cooling rate used in the equilibrium simulation was 2.8X 109-1.

(3) Performing cluster analysis on the artificial lens model according to the RMSD value of the overall structure characteristic to obtain the artificial lens model of each representative structure, and using the artificial lens model to simulate and test the material performance of a subsequent artificial lens model; the method comprises the following steps: refractive index, glass transition temperature, elongation, and solvent accessible area of the intraocular lens for representative structural intraocular lens models.

1) Simulated glass transition temperature and refractive index: the glass transition temperature is an inherent property of amorphous polymeric materials and can be obtained by molecular dynamics simulation under NPT conditions. By performing molecular dynamics simulation on the model structure of the artificial lens, the change of the specific volume with the temperature can be obtained, and therefore the value of the glass transition temperature can be obtained from the slope of the change. According to the Clustering analysis representative conformation, a system polarizability value under the condition that an electric field with certain intensity is applied in the xyz direction is calculated by using Gaussian16 software, and a refractive index value is obtained by analyzing and calculating through Mulfiwfn software (the calculation formula is as follows).

In the above formula, α is polarizability, ε is dielectric constant, v is volume, α _xx ，α _yy And alpha _zz For the polarizability of the investigated system after application of electric fields in x, y and z directions, respectively, n is the refractive index.

2) Stress-strain analysis: firstly, carrying out two-stage minimization calculation, namely limiting the coordinates of the material main body in the first stage and opening the limitation in the second stage to optimize the material main body and solvent molecules (water) in the system; secondly, directly heating the simulation system to 600K so as to enable the initially built structure to be fully relaxed at high temperature, and slowly cooling the simulation system from 600K to 240K after 50ns of simulation time; finally, equilibration was performed at a temperature of 310K and data collection calculations were performed.

3) Simulating the accessible area of the solvent of the crystal face of the molecular dynamics model, and judging whether the artificial lens generates a 'sparkling' phenomenon or not according to the accessible area of the solvent:

a. in the molecular dynamics simulation, the molecular dynamics model constructed above is subjected to a relatively fast annealing scheme, i.e., heating to 400K at a simulation temperature of 300K (room temperature) and performing a 50ns simulation at this temperature, and then, the simulation temperature is rapidly decreased to 300K, and the simulation is continued for 50ns at this temperature. Finally, clustering analysis is carried out on the track files obtained through simulation to obtain a representative structure (experimental simulation of flash acceleration) of simulated annealing, namely, the phenomenon of flash of temperature acceleration in the experiment is reproduced after the simulation duration of 100 ns.

b. Calculating the solvent accessible area of the artificial lens to evaluate the phenomenon of twinkling: and after the constructed artificial lens model is subjected to molecular dynamics simulation, performing clustering analysis to obtain a representative configuration to obtain artificial lens models with representative structures, and calculating the accessible area of the solvent according to the artificial lens models with the representative structures. If the structure of the artificial crystal material is loose, the accessible area value of the solvent is obviously increased after the rapid annealing simulation, so that the capability of accommodating solvent molecules in the structure is increased, and finally, the phenomenon of 'sparkle' can be caused.

Example 1

The embodiment of the application provides a test for verifying the screening method of the application by adopting the AcrySof intraocular lens, which specifically comprises the following steps:

monomer components of AcrySof intraocular lenses (Alcon, usa) are shown in table 1, and monomers and crosslinking agents of AcrySof intraocular lenses are obtained from the literature. AcrySof intraocular lens systems contain two types of components: (1) a polymer chain a consisting of phenylethyl acrylate (PEA) and phenylethyl methacrylate (PEMA) structural units randomly; (2) polymer chain b consisting randomly of PEA, PEMA and butanediol diacrylate (BDDA). PEA and PEMA building blocks are crosslinked by BDDA. Given the size of the model and the computational resources required for subsequent simulations, the examples herein provide that the polymer chain lengths of components a and b do not exceed 20. The polymer chains of a and B were first created from Gaussian View and then geometrically optimized using the density functional theory and the Gaussian16 B.01 program, using the B3LYP functional, 6-31G (d) basis set for all atoms. The optimized structure of the polymer chain was filled into an AcrySof intraocular lens model using PackMOL software, which was selected as the starting point for subsequent molecular dynamics simulation, and the intraocular lens model was constructed with a full atom model structure as shown in fig. 1.

TABLE 1

Examples	Intraocular lens	Monomer	Crosslinking agent
					1	AcrySof intraocular lens	PEA and PEMA	BDDA
2	Sensar intraocular lens	TFEMA, EA and EMA	EG-DMA
				3	enVista intraocular lens	PEG-PEA, HEMA and Styrene	EG-DMA

Example 2

The embodiment of the application provides a test for verifying the screening method by using a Sensar intraocular lens, which specifically comprises the following steps:

monomer composition of the Sensar intraocular lens (Johnson & Johnson company, usa) the monomer and the crosslinking agent of the Sensar intraocular lens were obtained from the literature as shown in table 1. The Sensar intraocular lens system comprises two types of components: (1) a polymer chain randomly composed of 2,2, 2-trifluoroethyl methacrylate (TFEMA), Ethyl Acrylate (EA) and Ethyl Methacrylate (EMA) structural units; (2) polymer chains b consisting of TFEMA, EA, EMA and ethylene glycol dimethacrylate (EG-DMA) at random. And the TFEMA, EA and EMA structural units are crosslinked through EG-DMA. Given the size of the model and the computational resources required for subsequent simulations, the examples herein provide that the polymer chain lengths of components a and b do not exceed 20. The polymer chains of a and B were first created from Gaussian View and then geometrically optimized using the density functional theory and the Gaussian16 B.01 program, using the B3LYP functional, 6-31G (d) basis set for all atoms. The optimized structure of the polymer chains was filled into a Sensar intraocular lens model using PackMOL software, which was selected as the starting point for subsequent molecular dynamics simulations, and the full atom model structure was constructed for the intraocular lens model as shown in fig. 2.

Example 3

The embodiment of the application provides a test for verifying the screening method of the application by adopting an enVista intraocular lens, which specifically comprises the following steps:

monomer compositions of enVista intraocular lenses (Bausch & Lomb company, usa) are shown in table 1, and monomers and cross-linking agents of enVista intraocular lenses are available from the literature. The enVista intraocular lens system contains two types of components: (1) a polymer chain a randomly composed of polyethylene glycol phenyl ether acrylate (PEG-PEA), 2-hydroxyethyl methacrylate (HEMA) and Styrene (Styrene) structural units; (2) and (b) a polymer chain randomly composed of PEG-PEA, HEMA, Styrene and EG-DMA. PEG-PEA, HEMA, Styrene building blocks are crosslinked by EG-DMA. Given the size of the model and the computational resources required for subsequent simulations, the examples herein provide that the polymer chain lengths of components a and b do not exceed 20. The polymer chains of a and B were first created from Gaussian View and then geometrically optimized using the density functional theory and the Gaussian16 B.01 program, using the B3LYP functional, 6-31G (d) basis set for all atoms. The optimized structure of the polymer chain was filled into an enVista intraocular lens model using PackMOL software, which was selected as the starting point for subsequent molecular dynamics simulation, and the intraocular lens model was constructed with a full atom model structure as shown in fig. 3.

Example 4

The embodiment of the application provides a simulation of glass transition temperature and refractive index to the model of embodiment 1 ~ 3, specifically includes:

molecular dynamics modeling in example 1-example 3 intraocular lens models molecular dynamics simulations were performed using the AMBER universal force field (version 2.11, 2016 month 5) (GAFF2) of organic molecules. The AMBER force field type in GAFF2 can correctly describe the bonding and non-bonding interactions of polymer-related systems. The topology files necessary for the molecular dynamics simulation were prepared by the Antechamber module of the AMBER20 software. The intraocular lens model was solvated in an octahedral periodic box with a TIP3P water model, with the choice of the particular atoms between the outermost intraocular lens model and the walls of the simulated box

Distance.

Wherein, the molecular dynamics simulation of 500ns is performed, and the trajectory file contains 250000 frames. On the basis of cluster analysis, the frames are clustered into groups, the structures in each group having the same structural features. The clustering analysis adopts an average linkage algorithm. In the analysis process, the structure represented by each frame represents its own cluster at the beginning of the analysis, and in the next iteration, two clusters with a short distance are merged into the same cluster. In the iterative process, if the required number of clusters n (n-5) has been obtained, the calculation is stopped. The distance between cluster a and cluster B is defined as: the average of all the distances between a and b, where a (b) is the framework structure in cluster a (b). Through clustering analysis, a molecular dynamics model of the artificial lens model of each representative structure can be obtained for simulating and testing the material performance of the subsequent artificial lens model.

The glass transition temperature refers to the temperature at which a polymeric material transitions from a glassy state to a highly elastic state. The temperature range selected in the examples of the present application is 200K to 400K with an interval of 20K. The equilibrium structures of the three intraocular lens models obtained in examples 1 to 3 were used as the starting point for the glass transition temperature simulation by molecular dynamics simulation. Data collection was performed at each target temperature over a 50ns simulation period under NPT conditions. This was in agreement with the actual values for each intraocular lens, as shown in table 2.

The results of the three intraocular lens models of examples 1-3 were subjected to cluster analysis by the molecular dynamics simulation described above. And calculating the polarizability value of the system under a certain strength electric field applied in the xyz direction by using Gaussian16 software according to the obtained representative conformation of each intraocular lens model. Finally, the refractive index values obtained by the analysis and calculation of the Mulfiwfn software have a trend more consistent with the actual values of the artificial lenses, as shown in table 3.

TABLE 2 results of simulated and actual glass transition temperature values

TABLE 3 results of simulated and actual values of refractive index

Intraocular lens	Analog value	Actual value
			AcrySof intraocular lens	1.228	1.555
Sensar intraocular lens	1.211	1.470
			Envista intraocular lens	1.374	1.540

Example 5

The embodiment of the application provides a simulation for performing stress-strain analysis on the model of the embodiment 1-3, which specifically comprises the following steps:

a stress-strain curve may be used to describe the relationship between the strain of a material under external tension (or compression) and an external force. The good tensile capacity of the intraocular lens enables the lens to fold without cracking, tearing or splitting and to recover quickly after implantation. Stress-strain analysis of the intraocular lens model was performed by LAMMPS software. To use the AMBER GAFF2 force field in the LAMMPS software, an InterMol software package was used for format conversion from AMBER topology files to lamps 21028168S data files. Uniaxial compression simulations generated stress-strain curves for the intraocular lens model. By reducing the z-direction dimension of the simulation box at a constant rate in the Nσ x σ yT set, a stress-strain curve can be obtained, the deformation ratio used in the simulation being 4.5 × 10 ^-3 ps ^-1 . Examples 1-3 the stress-strain curves for the three lenses are shown in fig. 4, where the Sensar lenses have greater tensile strength and modulus of elasticity than the AcrySof and enVista lenses, but have slightly lower elongation rates and a more consistent trend than the actual values for the corresponding lenses.

Example 6

The embodiment of the application provides the reappearance and analysis simulation of the 'flash' phenomenon on the computational simulation level for the models of embodiments 1-3, which specifically comprises the following steps:

through molecular dynamics simulation, a simulated annealing process was constructed: starting from a representative structure at room temperature (300K), the simulated temperature was rapidly increased to 400K, and a 50ns simulation was performed at this temperature. Subsequently, the simulated temperature was rapidly decreased to 300K, at which temperature the simulation was continued for 50 ns. Finally, a representative structure of simulated annealing (flash accelerated experimental simulation) is obtained by performing cluster analysis on the track file obtained by simulation. By comparing the cavities present in the model structures of examples 1-3, solvent accessible surface analysis was performed on representative structures generated by cluster analysis, with the results shown in table 4. The difference between the accessible solvent surface of the Sensar intraocular lens and the enVista intraocular lens model structure before and after simulated annealing is small, while the accessible solvent surface of the AcrySof intraocular lens model structure before and after simulated annealing is obviously changed.

Actual AcrySof intraocular lens, Sensar intraocular lens and enVista intraocular lens were subjected to a glaring test, and the actual results are shown in fig. 6, where a is AcrySof SN60WF intraocular lens, B is Sensar AR40e intraocular lens, and C is enVista MX60 intraocular lens, and it is obvious that the tendency of variation of solvent accessible area of the intraocular lens in front and rear of the present application simulation is similar to the tendency of glaring phenomenon of the actual intraocular lens.

TABLE 4 solvent accessible area of intraocular lenses before and after sparkle simulation

Example 7

The embodiment of the application provides a molecular dynamics simulation for the models of embodiments 1 to 3 to obtain a corresponding RMSD result, which specifically includes:

the results of RMSD obtained from 500ns molecular dynamics simulations performed on the three iol model structures constructed in examples 1-3 are shown in fig. 5. The initial stage (from 0 to 50ns) RMSD values fluctuate widely for the Sensar and enVista systems. As the simulation time is further increased, the overall stability fluctuations of the RMSD values of both are smaller. However, the RMSD value of the AcrySof system increased rapidly in the initial stage and at the end of the simulation, indicating that the internal structure of the model changed significantly from the initial structure in the final simulation.

It can be seen that the deviation of the values obtained by simulation in tables 2 to 4 is within a reasonable range through repeated calculation and verification and literature verification, and the characteristics of the known intraocular lens model obtained by simulation in the embodiment of the present application are consistent with the trend of the data of the existing intraocular lens, and as shown in the tables, the deviation is not large, and the result obtained by simulation can be considered to be real and credible.

In summary, the effectiveness and accuracy of the screening method of the present application are verified by performing simulation analysis on the existing intraocular lens material and comparing the simulated analysis with the actual material characteristics (refractive index, glass transition temperature, stress strain, and induced flare formation). The embodiment of the application aims to provide an artificial lens material design and screening method and system based on molecular dynamics simulation, and provides a scheme for synthesizing an ideal artificial lens material.

The foregoing is only a preferred embodiment of the present application and it should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present application, and these improvements and modifications should also be considered as the protection scope of the present application.

Claims

1. A method of screening intraocular lens material comprising:

obtaining the molecular structural formula of a monomer and a cross-linking agent in the intraocular lens material to be screened and the dosage ratio of the monomer and the cross-linking agent;

performing molecular dynamics simulation on the optimized artificial lens model by using a molecular dynamics method to obtain an RMSD value of the overall structural characteristics of the artificial lens model;

and screening the intraocular lens material meeting the preset requirements from the intraocular lens materials to be screened according to the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens.

2. The screening method according to claim 1, wherein the intraocular lens material meeting the preset requirements is selected from the intraocular lens materials to be screened according to the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens, and specifically comprises:

3. The screening method according to claim 1,

the construction of the intraocular lens model specifically comprises:

the optimizing the intraocular lens model specifically comprises:

4. The screening method according to claim 1,

the molecular dynamics simulation of the optimized intraocular lens model specifically comprises the following steps:

5. The screening method according to claim 2, wherein the method of calculating the refractive index value includes: calculating the numerical value of the system polarizability under an electric field with preset intensity applied in the xyz direction by using Gaussian16 software for the representative structure artificial lens model, and obtaining the refractive index of the molecular dynamics model through the analysis and calculation of Mulfiwfn software.

6. The screening method according to claim 2, wherein the calculation method of the elongation rate comprises:

limiting coordinates of the representative structural intraocular lens model;

7. The screening method according to claim 2, wherein the calculating of the solvent accessible area of the intraocular lens comprises:

8. The screening method according to claim 2, wherein the preset range corresponding to the refractive index is 1.50 or more; the corresponding preset range of the glass transition temperature is 253.15K-298.15K; the preset range corresponding to the elongation is more than or equal to 150 percent; the solvent accessible area of the artificial lens is not more than the corresponding preset range

9. A system for screening intraocular lens material, comprising:

the analysis unit is specifically configured to: performing clustering analysis on the artificial lens model according to a track file obtained by the molecular simulation to obtain an artificial lens model with a representative structure;

the screening unit is specifically configured to: and screening the intraocular lens materials meeting the preset requirements from the intraocular lens materials to be screened according to the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens.

10. The screening system of claim 9,

the screening unit is specifically as follows: and taking the intraocular lens material to be screened, of which the refractive index, the glass transition temperature, the elongation and the solvent accessible area of the intraocular lens all accord with corresponding preset ranges, as the intraocular lens material which accords with preset requirements.