JP5344391B2 - Molecular model of protein molecule and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a molecular model enabling a user to simultaneously observe a molecule surface shape and an inner-molecule main-chain/side-chain structure of a protein molecule by using a three-dimensional molding device such as a 3D printer. <P>SOLUTION: On the basis of three-dimensional coordinates of an atom constituting protein obtained from a protein structure database, a molecule inner structure model and a molecule surface structure model adjusted to be the same reduction scale as that of the molecule inner structure model are prepared and, further, on the basis of the three-dimensional shape data of the molecule surface structure model, a mold model is prepared (step S1-S5). Molding input data created by arranging the molecule inner structure model in the mold model at a corresponding position and in a corresponding orientation is input to the three-dimensional molding device, and the molecule inner structure and the mold are integrally shaped (step S6, S7). A transparent resin is filled and cured in the shaped mold to form the molecule surface structure (step S8). By removing the mold (step S9) after the transparent resin is cured, the molecule model 100 is completed. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a molecular model expressing a three-dimensional structure of a protein or the like and a method for producing the same.

  Currently, research on structural biology that analyzes the function from the three-dimensional structure of proteins is actively conducted. For researchers in the field of structural biology, understanding the shape of a molecule spatially is very important for understanding and inferring the function of the molecule and for searching for target compounds.

  At present, as a method for three-dimensionally understanding the molecular structure of a protein, a virtual three-dimensional image model of a molecule is mainly constructed in a computer, and the image model is displayed on the computer display (two-dimensional screen). By rotating and displaying the images at various angles, the computer operator recognizes the three-dimensional information of the molecules in a pseudo manner. Software that realizes such a three-dimensional structure display of protein analysis technology is available for a fee or free of charge, and various display methods are available depending on the nature of the analysis object and the purpose of use (Non-patent Document 1). See).

  However, in order to recognize the three-dimensional molecular structure using the software of the prior art, it is necessary to constantly rotate the image model with a mouse or the like, and the rotation operation also requires the skill of the operator. Furthermore, it is difficult to convey the three-dimensional molecular image recognized on the display to others.

  Furthermore, from a more specialized point of view, the images displayed with conventional software are mainly “simplified” such as the main chain structure of the protein and the wire model, but the actual protein is the main chain, It consists of side chains, and the main chain structure forms secondary structures such as α-helix and β-sheet. These secondary structures are closely packed together, forming gaps and “molecular surface structures” for interaction with other molecules. In other words, obtaining three-dimensional information about the structure of the surface of the molecule as well as the structure of the main and side chains inside the molecule is very important for grasping functions such as protein enzyme reaction and molecular recognition.

  It is very difficult to capture this information intuitively with the above-mentioned software. The most intuitive way to grasp this information is to check the shape of the molecular surface by actually touching it, and to check the inner main chain and side. A molecular model that can grasp the three-dimensional position of the chain is most desirable, but no technique for producing such a molecular model has been proposed so far.

  In recent years, products called three-dimensional (3D) printers have been put on the market. As a result, an environment in which a three-dimensional structure virtually created in a computer can be prototyped with high accuracy, high speed and low cost (see Non-Patent Document 2)

  There is also a venture company that uses this 3D printer device to print (manufacture) and sell a three-dimensional model of a protein (see Non-Patent Document 3).

  However, the method for producing a molecular model disclosed in Non-Patent Document 3 is mainly a three-dimensional model of a main chain structure or a molecular surface structure, and the structures of both cannot be realized (visualized) at the same time. In addition to these modeling problems, the actually manufactured model is fragile because it simulates the fine structure of the protein, and it requires careful attention to its handling. There is a definite defect in nature for the purpose of actually touching it and grasping or discussing its detailed structure. In addition, it is naturally impossible to confirm the deformation state by slightly distorting the conventional model as described above.

  In addition, Patent Document 1 is disclosed as another molecular model manufacturing technique, but this technique includes a spherical or polyhedral atomic member made of plastic or foamed polystyrene, and the insertion of this member to be connected to this atomic member. It is a technique for producing a molecular model including a metal needle-like member inserted in the mouth, and is not a technique that can express the fine structure of a protein before the solution of the above problems.

JP 2004-309578 A

Kengo Kinoshita, 1 other person, “PDBjViewer (jV)”, [online], Japan Protein Structure Data Bank, [searched on January 29, 2009], Internet <URL: http://www.pdbj.org/PDBjViewer /index_j.html> “3D Printer Z Series”, [online], DICO Corporation, [searched on January 29, 2009], Internet <URL: http://www.di-co.jp/product/3d_printer/z_series/index. html> “3D Molecular Designs”, [online], 3D Molecular Designs LLC (3D Molecular Designs LLC), [searched on January 29, 2009], Internet <URL: http://3dmoleculardesigns.com/>

  Therefore, the present invention solves the conventional problems, a molecular model capable of simultaneously observing the molecular surface shape of protein molecules and the main chain / side chain structure inside the molecule using a three-dimensional modeling apparatus such as a 3D printer, An object is to provide a manufacturing method thereof.

  Furthermore, the present invention provides a molecular model of a protein molecule that is produced using a three-dimensional modeling apparatus such as a 3D printer, is robust in transportation and handling, and has a suitable molecular surface flexibility, and a method for producing the same. The purpose is to provide.

  The inventor of the present application pays attention to simultaneously giving a molecular surface structure and a molecular internal structure as three-dimensional solid information to be input to the three-dimensional modeling apparatus after intensive study, and (1) corresponds to the molecular surface structure. First, a molecular model model including a template model having a shape and a molecular internal structure model provided inside the template model is first constructed, and the template and the molecule inside are analyzed by a three-dimensional modeling apparatus based on the shape of the molecular model model. When a model with a structure is printed, and (2) a transparent resin is charged and cured in the space (gap) between the mold of this model and the internal structure of the molecule, a molecular surface structure made of a transparent resin, It has been found that a molecular model having a molecular internal structure modeled by a three-dimensional modeling apparatus can be produced, and the present invention has been completed.

That is, a method for producing a molecular model of a protein molecule in one embodiment of the present invention is as follows.
Preparing a molecular internal structure model based on the three-dimensional coordinate values of protein constituent atoms;
Preparing a molecular surface structure model adjusted to the same scale as the molecular internal structure model based on the three-dimensional coordinate values;
Preparing a template model based on the three-dimensional shape data of the molecular surface structure model;
Placing the molecular internal structure model in the template model based on the three-dimensional coordinate values;
Converting the molecular model model including the template model and the molecular internal structure model arranged in the arrangement step into a file format that can be recognized by the three-dimensional modeling apparatus and inputting the model input data to the three-dimensional modeling apparatus;
With the three-dimensional modeling apparatus, modeling the molecular internal structure and the mold integrally from the modeling input data;
Filling the mold with a transparent resin and curing to form a molecular surface structure;
Removing the mold after the transparent resin is cured.

In addition to the above steps, the molecular model production method of the present invention is preferably
The arranging step further prepares a support material model for coupling between the template model and the molecular internal structure model ,
The modeling step models a support material that integrally couples the molecular internal structure and the template together with the molecular model data including the support material model,
In the mold removing step, the support material is removed together with the mold.

In addition to the above steps, the molecular model production method of the present invention is preferably
The step of preparing the mold model further comprises the step of dividing the mold model into a mold body part model and a mold lid part model,
The modeling step forms a mold body part having an opening based on the mold body part model and the mold lid part model, and a mold lid part that covers the opening part,
The mold body is molded integrally with the molecular internal structure,
In the molecular surface structure formation step, the transparent resin is filled into the mold body through the opening, and the transparent resin is cured after the opening is covered with the mold lid.

In addition to the above steps, the molecular model production method of the present invention is preferably
The mold is a thin film structure.

In addition to the above steps, the molecular model production method of the present invention is preferably
The method further comprises a step of coloring the surface of the molecular surface structure with a clear color paint after the template removing step.

In addition to the above steps, the molecular model production method of the present invention is preferably
After the template removing step, the method further includes a step of applying a crystal modeling process to the molecular model to give information related to the molecular model.

  Moreover, the molecular model of the protein molecule of the present invention is provided by the above-described method for preparing a molecular model.

  Here, the “three-dimensional modeling apparatus” means an apparatus that models a three-dimensional object based on input information relating to the three-dimensional solid information of the object. For example, a 3D printer (powder fixing method, ultraviolet curing method, heat curing method, (Including 3D printers such as melt lamination) and NC lathes and 3D cutting RP (rapid prototyping) machines, but are not necessarily limited thereto.

  The term “model” used for terms such as “molecular internal structure model”, “molecular surface structure model”, “template model”, and “support material model” is three-dimensional solid information (data) that can be recognized by a computer. The information can be displayed in a virtual space on the computer screen using predetermined computer software as necessary. These models are converted into a predetermined file format and become input information necessary for the three-dimensional modeling apparatus to model an actual member corresponding to each model.

  Further, the “transparent resin” means a resin (transparent resin) that becomes a transparent body when it becomes a predetermined lump after curing, and the inside can be confirmed from the outside. Therefore, a resin which is a suspended color and whose internal state cannot be confirmed after curing is not suitable for the present invention. Examples of the resin raw material include hydrogels such as silicon resin (PDMS) and acrylic resin (PMMA), or acrylamide. PDMS is preferable in terms of having moderate elasticity and good transparency, and PMMA is preferable in terms of having high transparency and chemical stability such as hardness and extending the life of the molecular model. Moreover, since hydrogel can use water for the solvent for molecular model immersion mentioned later, it has the advantage that handling is easy.

  The molecular model of the protein molecule of the present invention and the method for producing the same according to the present invention have the following remarkable effects.

  According to the method for producing a molecular model of the present invention, in order to use a three-dimensional modeling apparatus such as a 3D printer, a highly accurate (about 0.1 mm according to the working accuracy of a 3D printer) and a complicated molecular internal structure and It becomes possible to easily provide a molecular model having a molecular surface structure.

  According to the method for producing a molecular model of the present invention, it is possible not only to provide a molecular model capable of simultaneously observing the molecular internal structure and the molecular surface structure of a protein at the same scale and in a corresponding positional relationship. Since it is made of an elastic material, it is possible to provide a molecular model that can confirm each deformation state. In addition, the molecular model that can confirm the deformation state of both structures is an induced fit of a protein by a substrate or a drug molecule (the three-dimensional structure of the active center changes when the substrate or the like is inductively matched to the active center of the enzyme protein) Phenomenon) and interaction between protein molecules, and so on.

  According to the method for producing a molecular model of the present invention, it is possible to provide a molecular model having both sufficient structural strength (robustness) and elasticity, so that it is not necessary to pay excessive attention to the handling of the molecular model. .

  According to the method for producing a molecular model of the present invention, it is only necessary to use a minimum amount of a template material necessary for forming a molecular surface structure, and it is possible to reduce the three-dimensional printing cost and the mold disposal cost after the model is completed. Can be suppressed.

It is the flowchart explaining the preparation methods of the molecular model 100 of this invention. It is the figure which demonstrated schematically the preparation methods of the molecular model 100 of this invention. It is the figure which showed an example of (a) molecular internal structure model 1 and (b) molecular surface structure model 2. FIG. (A) Template model 3 provided with a molecular internal structure model 1, and (b) an example of a cross-sectional state of the template model 3. The mold 30 and the molecular internal structure 10 of the molecular model 100 immediately after being printed by the 3D printer are shown. It is the figure which showed a mode that the molecular model 100 of this invention was immersed in the solvent.

  Hereinafter, although the present invention is explained based on an embodiment shown in a drawing, the present invention is not limited to the following concrete embodiment at all.

[Protein structure]
In general, the structure of a protein can be displayed as a three-dimensional coordinate value of each constituent atom determined by X-ray crystallography or NMR. Protein data bank (Protein Data Bank, PDB) is known as a database that provides protein-related information and three-dimensional structure information. In this data bank, each protein is stored as three-dimensional structure information of each protein. The three-dimensional coordinate value of each atom constituting is stored (registered) as a text file. At present, the number of atomic coordinate data such as proteins registered in the PDB exceeds 50,000.

All amino acids in protein molecules have a structure in which a hydrogen atom, -NH ₂ group, -COOH group, and a group that determines the type of amino acid called a side chain are bonded to a carbon atom (α-carbon) and bonded by dehydration condensation. (Peptide bond). A peptide-bonded chain excluding side chains is called a main chain, and a regular structure is often found in the main chain. This regular structure is called a secondary structure and is roughly divided into an α-helix and a β-sheet. That is, since the protein three-dimensional structure has a hierarchical structure of atom → amino acid → secondary structure, the three-dimensional structure of the main chain can be expressed as a secondary structure arrangement (packing).

[Molecular model production method]
FIG. 1 is a flowchart illustrating a method for producing a molecular model 100 according to the present invention. FIG. 2 is a diagram schematically illustrating the main steps of the flowchart shown in FIG. Note that each element in FIG. 2 is schematically shown for convenience of explanation.

  First, a three-dimensional coordinate value of a constituent atom related to a desired protein is acquired from a protein tertiary structure information database such as the PDB (step S1). The method for obtaining the three-dimensional coordinate value of the atom may be any method, but a desired protein is selected on a predetermined Internet site where the database is uploaded via the Internet, and the three-dimensional of atoms constituting the protein is selected. It is preferable from the viewpoint of simplicity and speed that it is realized by downloading the coordinate value to its own computer.

  Next, the internal structure model of the desired protein molecule is obtained from the obtained atomic coordinate information using computer software (Molecular Structure Viewer) that displays the 3D molecular model as computer graphics and allows editing and drawing of the molecular model. 1 is prepared (selected) (step S2). The selected molecular internal structure model 1 is drawn on the molecular structure viewer as necessary, and is output in a format that can be recognized by a 3D printer described later.

  Examples of the molecular structure viewer include PDBjViewer disclosed in Non-Patent Document 1, but are not necessarily limited thereto. Examples of other molecular structure viewers applicable to the production method of the present invention include MOLMOL, MOLSCRIPT, Swiss-Prot, Raster-3D, GRASP, and RasMol. The file format that can be recognized by the 3D printer includes VRML (Virtual Reality Modeling Language) at the present time, but is not limited to this. For example, a file for expressing X3D (XML-based 3D computer graphics) Format).

  Examples of the molecular internal structure model 1 include a ribbon model, a neon model, and a CPK model. Here, the “ribbon model” refers to a model that displays the main chain portion of a protein α-helix or β-sheet structure as a helical or linear ribbon, and the “neon model” refers to a covalent bond portion of a protein. Is represented as a thick cylindrical neon tube, and “CPK model” refers to a model in which protein atoms are represented by a sphere reflecting the size of the atomic radius. The English notation of the CPK model is New Corey-Pauling Space-Filling Atomic Models with Koltun Connectors.

  In the present invention, it is preferable to select a ribbon model when it is particularly desired to confirm and examine the packing in the secondary structure of the main chain (see FIGS. 2 and 3A). On the other hand, when confirmation of the side chain position of a specific residue is important, it is preferable to select a neon model or a CPK model. Furthermore, when both the main chain structure and the side chain position are important, a model in which a plurality of the above models are selected and combined may be drawn. You may make it draw by coloring.

  Next, using the molecular structure viewer described above, a protein molecular surface structure model 2 adjusted to the same scale as the molecular internal structure model 1 based on the atomic coordinate information acquired in step S1 is prepared ( Step S3). The protein molecule surface structure model 2 includes a CPK model (a model reflecting the size (radius) of protein constituent atoms), a van der Waals model (a model reflecting the van der Waals radius), and water molecule exclusion. Model, etc. In the present invention, it is preferable to select a water molecule exclusion model because it is particularly easy to process such as mold formation and filling with a transparent resin, and is often used conventionally (FIG. 3B). See).

  Furthermore, a template model 3 of the molecular surface structure model 2 is prepared based on the three-dimensional shape data related to the molecular surface structure model 2 using 3D modeling software (step S4). Here, the 3D modeling software is software for performing fine defect correction and artificial processing before actual modeling (printing) by a 3D printer or the like, and is sold together with a 3D modeling apparatus such as a 3D printer, for example. However, the present invention is not limited to this as long as the above-described fine correction and processing are possible.

  Specifically, the molecular surface structure model 2 is read into the 3D modeling software, and the interior defined by the outer surface (contour) of the molecular surface structure model 2 is defined as a space on the 3D modeling software, and the outer surface is surrounded. The mold model 3 is completed by constructing the structural model of the shape. In particular, as the template model 3, a thin film body having a predetermined thickness (wall thickness) from the outer surface along the outer surface of the molecular surface structure model 2 (the template model 3 in FIG. 2 and FIG. 4B). ), Which is very preferable from the viewpoint of easy destruction / exclusion of the template 30 from the molecular model 100 described later. Here, the thickness of the thin film body model may be a thickness that can provide a strength capable of holding the mold structure in the execution of the printing step and the resin filling / curing step described below, and is, for example, a mold model of about 100 mm × 100 mm × 100 mm. In the case of 3, the thickness is preferably set to about 1 to 2 mm. This not only facilitates the removal of the mold 30 from the molecular model 100, but also minimizes the printing cost and the disposal cost of the mold because only a minimum amount of the mold material is required (particularly in the case of a structure in a 3D printer). The cost of printing an object or the like is proportional to the volume of the structure that is the printing object).

  The molecular surface structure model 2 is used only for forming the template model 3 in the production method of the present invention, that is, the template model 3 is combined with the molecular internal structure model 1 in the steps after step S4. 100 will be used.

  After that, in the 3D modeling software, the molecular internal structure model 1 selected in step S2 is read, and the molecular internal structure model 1 is arranged based on the atomic coordinate values (absolute coordinate values) in the template model 3 whose inner surface forms the molecular surface shape. (Superimpose) (step S5). Thereby, the molecular internal structure model 1 having a positional relationship (same position / orientation) appropriately corresponding to the molecular surface shape in the template model 3 is provided in the template model 3 (FIG. 4A). See).

  Normally, a space 2a exists between the template model 3 and the molecular internal structure model 1 (see the portion to be a molecular surface structure, see FIG. 4B), and the molecular internal structure model 1 is a wire shape. The molecular internal structure portion 10 of the molecular model 100 three-dimensionally printed by a 3D printer, which will be described later, becomes a fragile structure. Accordingly, as shown in FIG. 2, a support material model 4 that supports and reinforces the molecular internal structure model 1 in the template model 3 is further installed between the template model 3 and the molecular internal structure model 1 (step S5a). . As a result, in the 3D modeling software, the molecular internal structure model 1, the template model 3, and the support material model 4 are all in a complex state but are connected to each other, and are modeled as an integral structure by a 3D printer described later ( Printing). The support material model 4 may be, for example, a rod-like body, and it is desirable to install the support material model 4 at a location where the structure (strength) of the molecular internal structure model 1 is weak so as to be orthogonal to the inner surface of the mold model 3.

  In addition, as shown in FIG. 2, the mold model 3 is divided into a mold body model 3a and a mold lid model 3b (step S5b). The reason why the template model 3 is divided in this way is to allow the molecular internal structure 10 provided in the template 30 to be physically printed in the later-described three-dimensional printing step S7 as well as the resin described later. This is because the resin inlet (opening) 30c is formed also in the filling step S8. For example, when the outer shell of the mold 30 is completely covered like an egg, depending on the type of 3D printer, after the molecular internal structure 10 is printed, powder generated in the printing process remains in the mold 30 and is discharged. Since there may be a problem that (removal) cannot be performed, it is better to provide at least one opening 30c in the mold 30. Also, a plurality of mold lid models 3b may be prepared, and in this way, a plurality of openings 30c can be installed in the mold 30 after 3D printer printing. One of the plurality of openings 30c can be used as a hole for filling the transparent resin, and the other can be used as an air hole for promoting the filling of the transparent resin.

  Next, the molecular model including the mold body part model 3a, the support material model 4 and the molecular internal structure model 1 that has been edited is converted into a file format that can be recognized by a three-dimensional printer, and used as modeling input data. Input to the three-dimensional printer (step S6).

  Next, the molecular internal structure 10 having a shape corresponding to these is input from the input data (modeling input data) of the molecular model model including the mold body model 3a, the support material model 4 and the molecular internal structure model 1 by a three-dimensional printer. The support member 40 and the mold body 30a are integrally formed (step S7). In addition, it is preferable to print the molecular internal structure 10 with a highly plastic material (ink) based on starch from the viewpoint of imparting elasticity. FIG. 5 shows the template 30 and the molecular internal structure 10 of the molecular model 100 immediately after being printed by the 3D printer. Here, for convenience, the template 30 is divided so that the molecular internal structure 10 can be observed. Moreover, the support material 40 which supports several molecular internal structures 10 from FIG. 5 can also be confirmed.

  In addition, the mold lid 30b corresponding to this shape is formed from the input data of the mold lid model 3b by a three-dimensional printer (step S7a).

  After the three-dimensional printing steps S7 and S7a, the transparent resin is poured into the mold main body 30a through the opening 30c in the mold main body 30a (the part associated (fitted) with the mold lid 30b) and cured (step S8). ). As a result, the space 2 a in the mold body 30 a is filled in a state including the molecular internal structure 10, thereby forming the molecular surface structure 20. In addition, it is preferable to cover the opening 30c with the mold lid portion 30b after the transparent resin is filled until it is cured (step S8a), whereby the molecular surface structure 20 has a more accurate shape.

  Here, the transparent resin to be filled is preferably a hydrogel such as silicon resin (PDMS), acrylic resin (PMMA), or acrylamide. PDMS is advantageous in that it has moderate elasticity and good transparency. In particular, elasticity is advantageous in deforming the completed molecular model 100. The molecular model 100 having the molecular internal structure 10 printed with the above-described highly plastic material and the molecular surface structure made of an elastic transparent resin can be easily deformed. When examining the association and the substrate binding, it is possible to confirm a state in which the molecular model 100 is slightly deformed while holding the molecular model 100 in hand. PMMA is advantageous in that the lifetime of the molecular model 100 is expected to be extended due to its high transparency and chemical stability such as hardness. Moreover, since hydrogel can use water for the solvent for immersion observation of the molecular model 100 mentioned later, it has the advantage that handling is easy.

  After the transparent resin filling / curing step S8, the mold 30 (the mold body 30a and the mold lid 30b) and the support member 40 are removed (step S9). As described above, if the mold 30 is formed of a thin film body having a predetermined thickness, the mold 30 can be easily broken and removed. Here, a resin may be further filled and cured in the cavity 40a in the molecular surface structure 20 generated by removing the support material 40 (step S9a).

  As described above, the molecular internal structure 10 (main chain / side chain) is appropriately arranged and oriented in the transparent resin, and the portion including the resin surface and surrounding the molecular internal structure 10 forms the molecular surface structure 20 of the present invention. The molecular model 100 is completed.

  Furthermore, you may perform an additional modeling process with respect to resin after hardening (step S10). For example, a resin may be irradiated with a laser beam using a crystal shaping apparatus or the like to form cracks inside the resin, and information related to the molecular model 100 (hydrogen bond type and index number) may be engraved stereospecifically. (Step S10a). In addition, when there are a plurality of molecular models 100, a transparent resin surface may be colored with a single clear color paint (a paint with transparency) for the purpose of easily identifying each model 100. The color may be colored using a plurality of color paints so as to reflect the degree of hydrophilicity and hydrophobicity on the molecular surface, the electrostatic potential, and the like. (Step S10b).

[Molecular model observation method]
The use / observation method of the molecular model of the protein molecule of the present invention produced as described above will be described below.

Observation of a molecular model in the air The molecular model 100 can be observed by hand and deformed in the air, which is very useful when examining protein association and substrate binding. However, in air having a lower refractive index than the resin (refractive index: about 1.00), it may be difficult to correctly see the main chain and side chain structure (molecular internal structure 10) inside the resin.

Observation of molecular model immersed in solvent As another observation method, molecular model 100 is used in a solvent (water solvent or solvent other than water) adjusted to have the same refractive index as that of the resin before curing or the resin after curing. You may observe in the state immersed. In addition, when hydrogel is used for the transparent resin of the present invention, since the refractive index of the resin is close to water (refractive index: about 1.33), an aqueous solvent (including water itself) may be used. it can. When an aqueous solvent is used, there is an advantage that handling is easy because the model is taken out and rinsed with water. In the case of a molecular model having another resin material (a resin material having a higher refractive index than that of hydrogel), the refractive index of the aqueous solvent can be adjusted to the resin material by adjusting the concentration of the aqueous solvent. That's fine. Examples of the solute having a high refractive index that is dissolved in an aqueous solvent include saccharides, salts, and glycerin (shown by the formula C ₃ H ₅ (OH) ₃ ). The refractive index can be adjusted in the range of about 1.33 to 1.50 by changing the concentration of the solute in this way. Examples of the solvent other than water include silicone oil (refractive index of 1.40 which is the same as that of PDMS), vegetable oil / mineral oil (refractive index of about 1.48 similar to acrylic resin), and the like.

  By this observation method, since the refractive indexes of the transparent resin and the solvent are almost equal, the configuration of the main chain and the side chain as the molecular internal structure 10 inside the resin can be observed more clearly. . Further, if the transparent resin surface is colored with a clear color paint in the additional modeling step S10b described above, the molecular internal structure 10 can be seen through the resin while seeing the shape of the molecular surface structure three-dimensionally even after immersion. It is also possible to see. If the solvent to be immersed is an aqueous solution mainly composed of water, it is only necessary to rinse with water when taking out the molecular model 100 from the solvent after observation, which is advantageous in terms of washing, storage, handling, and the like. is there.

  FIG. 6 shows a state in which the molecular model 100 produced according to the present invention is immersed in a solvent. Vegetable oil was used as the solvent. Although FIG. 6 is a gray scale image, the surface of the molecular surface structure 20 of the molecular model 100 is actually colored with a green clear color paint. From FIG. 6, by observing in a solvent adjusted to the same refractive index as the transparent resin, the molecular surface structure 20 and the molecular internal structure 10 can be recognized more clearly, and the transparent resin is colored with a clear color paint. It can be seen that the contour of the molecular surface structure 20 can be recognized more clearly.

  The method for producing a molecular model and the produced molecular model of the present invention described above have the following effects.

  According to the method for producing a molecular model of the present invention, in order to use a three-dimensional modeling apparatus such as a 3D printer, a highly accurate (about 0.1 mm according to the working accuracy of a 3D printer) and a complicated molecular internal structure and It becomes possible to easily provide a molecular model having a molecular surface structure.

  According to the method for producing a molecular model of the present invention, it is possible not only to provide a molecular model capable of simultaneously observing the molecular internal structure and the molecular surface structure of a protein at the same scale and in a corresponding positional relationship. Since it is made of an elastic material, it is possible to provide a molecular model that can confirm each deformation state. In addition, the molecular model that can confirm the deformation state of both structures is an induced fit of a protein by a substrate or a drug molecule (the three-dimensional structure of the active center changes when the substrate or the like is inductively matched to the active center of the enzyme protein) Phenomenon) and protein-protein interactions.

  According to the method for producing a molecular model of the present invention, it is possible to provide a molecular model having both sufficient structural strength (robustness) and elasticity, so that it is not necessary to pay excessive attention to the handling of the molecular model. .

  According to the method for producing a molecular model of the present invention, it is only necessary to use a minimum amount of a template material necessary for forming a molecular surface structure, and it is possible to reduce the three-dimensional printing cost and the mold disposal cost after the model is completed. Can be suppressed.

  The molecular model provided by the present invention has heretofore been difficult to study only by looking at a computer screen. (1) Possibility of interaction with other molecules based on the three-dimensional characteristics in the molecular structure (drug screening) , (2) Prediction of binding mode, (3) Study of restriction of action of specific molecules from the viewpoint of three-dimensional structure, etc., and is expected to contribute academically as a tool in the fields of pharmacy and life science. is there. Therefore, the molecular model of the present invention is expected to be used mainly in higher research institutions such as universities, public testing research institutions, and pharmaceutical company laboratories.

  Furthermore, the present invention is compatible with the special characteristics of protein molecules, such that protein molecules have a fragile internal structure because they are fine and complex, and the molecular surface structure can be expressed in another manner. Although it is a manufacturing method of a molecular model, it is not necessarily limited to this, It can apply to preparation of the model of various fields. For example, the present invention may be applied to a method for producing a building model including an internal structure of a building and an external structure made of a transparent resin that includes the internal structure.

DESCRIPTION OF SYMBOLS 1 Molecule internal structure model 2 Molecule surface structure model 2a Space 3 Template model 3a Mold body part model 3b Mold lid part model 3c Mold body part model opening 4 Support material model 10 Molecule internal structure 20 Molecule surface structure 30 Mold 30a Template body Part 30b Mold lid part 30c Opening part of mold body part 40 Support material 40a Cavity generated by removing support material 100 Molecular model

Claims (7)

Preparing a molecular internal structure model based on the three-dimensional coordinate values of protein constituent atoms;
Preparing a molecular surface structure model adjusted to the same scale as the molecular internal structure model based on the three-dimensional coordinate values;
Preparing a template model based on the three-dimensional shape data of the molecular surface structure model;
Placing the molecular internal structure model in the template model based on the three-dimensional coordinate values;
Converting the molecular model model including the template model and the molecular internal structure model arranged in the arrangement step into a file format that can be recognized by the three-dimensional modeling apparatus and inputting the model input data to the three-dimensional modeling apparatus;
With the three-dimensional modeling apparatus, modeling the molecular internal structure and the mold integrally from the modeling input data;
Filling the mold with a transparent resin and curing to form a molecular surface structure;
Removing the mold after the transparent resin is cured;
A method for producing a molecular model of a protein molecule comprising The arranging step further prepares a support material model for coupling between the template model and the molecular internal structure model ,
The modeling step models a support material that integrally couples the molecular internal structure and the template together with the molecular model data including the support material model,
The method for producing a molecular model according to claim 1, wherein the template removing step removes the support material together with the template. The step of preparing the mold model further comprises the step of dividing the mold model into a mold body part model and a mold lid part model,
The modeling step forms a mold body part having an opening based on the mold body part model and the mold lid part model, and a mold lid part that covers the opening part,
The mold body is molded integrally with the molecular internal structure,
The molecular surface structure forming step is characterized in that the transparent resin is filled in the mold body through the opening, and the transparent resin is cured after the opening is covered with the mold lid. 3. A method for producing the molecular model according to 1 or 2.   The method for producing a molecular model according to any one of claims 1 to 3, wherein the template is a thin film structure. The method for producing a molecular model according to any one of claims 1 to 4, further comprising a step of coloring the surface of the molecular surface structure with a clear color paint after the template removing step.   6. The method according to claim 1, further comprising, after the template removal step, performing a crystal modeling process on the molecular model to give information related to the molecular model. How to make a molecular model.   The molecular model of the protein molecule produced by the production method of the molecular model of any one of Claims 1-6.