Initial structure generation apparatus, initial structure generation method, and initial structure generation program

Abstract

To optimize the search range when searching for a stable structure of a cyclic peptide molecule.SOLUTION: An initial structure generation device is provided, comprising: a generation unit configured to generate a model representing a cyclic peptide molecule by identifying a Cα atom of each of multiple amino acid residues, placing the identified multiple Cα atoms on a circumference, and then adding main chains and side chains of the multiple amino acid residues; and a search instruction unit configured to instruct a search unit to search for a stable structure of the cyclic peptide molecule using the generated model as an initial structure of the cyclic peptide molecule.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This invention relates to an initial structure generation apparatus, an initial structure generation method, and an initial structure generation program. [Background technology]

[0002] In recent years, in the field of drug discovery, there has been growing interest in drug discovery using medium-sized molecules (molecular weight 500-3000) with fewer side effects, and the development of search methods for exploring stable structures of these medium-sized molecules is progressing.

[0003] In particular, cyclic peptide molecules are attracting considerable attention because cyclization significantly reduces entropy, allowing for the creation of compounds with high binding activity. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2010-159218 [Patent Document 2] Japanese Patent Publication No. 2020-091518 [Patent Document 3] U.S. Patent Application Publication No. 2018 / 0260517 [Non-patent literature]

[0005] [Non-Patent Document 1] F. Jiang and H. Geng, "Computational Methods for Studying Conformational Behaviors of Cyclic Peptides", 2019 [Overview of the project] [Problems that the invention aims to solve]

[0006] In the search for a stable structure, it is important to search within an appropriate search range, and whether or not the search range can be optimized largely depends on the initial structure.

[0007] On the other hand, in the case of cyclic peptide molecules, the initial structure has so far been generated by cyclizing a linear peptide molecule by connecting the beginning and end. As a result, the generated initial structure has a low degree of freedom in the sequence of each amino acid residue constituting the cyclic peptide molecule, making it difficult to search for an appropriate search range when searching for a stable structure.

[0008] One aspect of this approach is to optimize the search range when searching for stable structures of cyclic peptide molecules. [Means for solving the problem]

[0009] According to one embodiment, the initial structure generation apparatus is Identify the Cα atom of each of the multiple amino acid residues, and each of the identified Cα atoms The radius is calculated based on the specified distance between adjacent Cα atoms. circumference along A generation unit that generates a model representing a cyclic peptide molecule by adding the main chain and side chains of the plurality of amino acid residues after arrangement, The system includes a search instruction unit that instructs the search unit to search for a stable structure of the cyclic peptide molecule using the generated model as the initial structure of the cyclic peptide molecule. [Effects of the Invention]

[0010] This allows for optimizing the search range when searching for stable structures of cyclic peptide molecules. [Brief explanation of the drawing]

[0011] [Figure 1] This figure shows an example of the system configuration, terminal device, and server device functional configuration of a stable structure search system. [Figure 2] This figure shows an example of the hardware configuration of terminal and server devices. [Figure 3]It is a diagram showing an example of the functional configuration of a cyclic peptide molecule generation unit. [Figure 4] It is a diagram showing a specific example of the processing of a Cα atom arrangement unit. [Figure 5] It is a diagram showing a specific example of the processing of an addition unit and a structure relaxation unit. [Figure 6] It is a diagram for explaining the dihedral angles of a backbone. [Figure 7] It is a first diagram showing an example of a dihedral angle distribution diagram. [Figure 8] It is a second diagram showing an example of a dihedral angle distribution diagram. [Figure 9] It is a flowchart showing the flow of a stable structure search process.

Mode for Carrying Out the Invention

[0012] Hereinafter, each embodiment will be described with reference to the accompanying drawings. In the present specification and the drawings, components having substantially the same functional configuration are denoted by the same reference numerals, and redundant descriptions are omitted.

[0013] [First Embodiment] <System Configuration of Stable Structure Search System, Functional Configuration of Terminal Device and Server Device> First, the system configuration of the stable structure search system according to the first embodiment and the functional configurations of the terminal device and the server device constituting the stable structure search system will be described. FIG. 1 is a diagram showing an example of the system configuration of the stable structure search system, the functional configurations of the terminal device and the server device.

[0014] The stable structure search system 100 is a system for searching for the stable structure of a medium molecule, and in particular, is a system for searching for the stable structure of a cyclic peptide molecule having a plurality of amino acid residue sequences.

[0015] As shown in FIG. 1, the stable structure search system 100 includes a terminal device 110, which is an example of an initial structure generation device, and a server device 120.

[0016] The terminal device 110 has a search program installed, and when this program is executed, the terminal device 110 functions as an amino acid residue sequence acquisition unit 111, a cyclic peptide molecule generation unit 112, a dihedral angle distribution calculation unit 113, and a stable structure output unit 114.

[0017] The amino acid residue sequence acquisition unit 111 is an example of an acquisition unit, and acquires the sequence of multiple amino acid residues constituting a cyclic peptide molecule to be searched when a user of the stable structure search system 100 inputs this sequence.

[0018] Furthermore, the amino acid residue sequence acquisition unit 111 acquires the parameters (distance "a") used to generate the initial structure of the cyclic peptide molecule to be searched, when the user of the stable structure search system 100 inputs these parameters.

[0019] The cyclic peptide molecule generation unit 112 is an example of a generation unit, and based on multiple amino acid residue sequences obtained by the amino acid residue sequence acquisition unit 111, it generates a model representing a cyclic peptide molecule under the obtained parameters, which serves as the initial structure of the cyclic peptide molecule. Furthermore, the cyclic peptide molecule generation unit 112 is an example of a search instruction unit, and by transmitting information indicating the initial structure of the generated cyclic peptide molecule to the server device 120, it instructs the server device 120 to search for a stable structure based on the initial structure. Details of the method for generating the initial structure of a cyclic peptide molecule by the cyclic peptide molecule generation unit 112 will be described later.

[0020] The dihedral angle distribution calculation unit 113 is an example of a calculation unit. In response to the transmission of information indicating the initial structure of the cyclic peptide molecule by the cyclic peptide molecule generation unit 112, it obtains information indicating the dihedral angles of the backbone calculated during the stable structure search process from the server device 120. The dihedral angle distribution calculation unit 113 also calculates the dihedral angle distribution based on the obtained information indicating the dihedral angles of the backbone and outputs a dihedral angle distribution diagram.

[0021] In response to the transmission of information indicating the initial structure of the cyclic peptide molecule by the cyclic peptide molecule generation unit 112, the stable structure output unit 114 obtains information indicating the stable structure of the searched cyclic peptide molecule from the server device 120. The stable structure output unit 114 also outputs information indicating the stable structure of the obtained cyclic peptide molecule.

[0022] The server device 120 functions as a stable structure search unit 121. The stable structure search unit 121 is an example of a search unit, and upon receiving information from the terminal device 110 indicating the initial structure of a cyclic peptide molecule, it searches for a stable structure of the cyclic peptide molecule based on the received information. The stable structure search unit 121 also transmits to the terminal device 110 information indicating the dihedral angle of the backbone calculated during the stable structure search process. Furthermore, the stable structure search unit 121 transmits to the terminal device 110 information indicating the stable structure of the searched cyclic peptide molecule.

[0023] The stable structure search unit 121 searches for a stable structure based on information indicating the initial structure of the cyclic peptide molecule transmitted from the terminal device 110, for example, by an extended ensemble method. The extended ensemble method here includes, for example, the multi-canonical method, the tempering method, and the replica exchange method (specifically, REST (Replica exchange with solute tempering)²).

[0024] <Hardware configuration of terminal and server devices> Next, the hardware configuration of the terminal device 110 will be described. Figure 2 shows an example of the hardware configuration of the terminal device and the server device.

[0025] (1) Hardware configuration of terminal device As shown in Figure 2(a), the terminal device 110 includes a processor 201, memory 202, auxiliary storage device 203, I / F (Interface) device 204, communication device 205, and drive device 206. The hardware components of the terminal device 110 are interconnected via a bus 207.

[0026] The processor 201 has various computing devices such as a CPU (Central Processing Unit) and a GPU (Graphics Processing Unit). The processor 201 reads various programs (for example, search programs, etc.) into memory 202 and executes them.

[0027] Memory 202 has main memory devices such as ROM (Read Only Memory) and RAM (Random Access Memory). The processor 201 and memory 202 form a so-called computer, and the computer realizes the above-mentioned functions by having the processor 201 execute various programs read from memory 202.

[0028] The auxiliary storage device 203 stores various programs and various information used when those programs are executed by the processor 201.

[0029] The I / F device 204 is a connection device that connects the operating device 211 and output device 212, which are examples of external devices, to the terminal device 110.

[0030] The communication device 205 is a communication device for communicating with the server device 120 via the network.

[0031] The drive device 206 is a device for setting the recording medium 213. The recording medium 213 here includes media that record information optically, electrically, or magnetically, such as CD-ROMs, flexible disks, and magneto-optical disks. The recording medium 213 may also include semiconductor memory that records information electrically, such as ROMs and flash memory.

[0032] The various programs to be installed on the auxiliary storage device 203 are installed, for example, when the distributed recording medium 213 is set in the drive device 206 and the various programs recorded on the recording medium 213 are read by the drive device 206. Alternatively, the various programs to be installed on the auxiliary storage device 203 may be installed by downloading them from the network via the communication device 205.

[0033] (2) Hardware configuration of the server device As shown in Figure 2(b), the server device 120 is configured as a cluster of multiple units, and each server device has a processor 221, memory 222, auxiliary storage device 223, I / F (Interface) device 224, communication device 225, and drive device 226.

[0034] Since the hardware components of each server device are the same as those of the terminal device 110, a detailed explanation is omitted here.

[0035] <Functional structure of the cyclic peptide molecule generation section> Next, the details of the functional configuration of the cyclic peptide molecule generation unit 112 will be described. As mentioned above, the various functions of the terminal device 110 are realized when the exploration program is executed by the terminal device 110. Of these, the cyclic peptide molecule generation unit 112 is realized in particular when the initial structure generation program, which is part of the exploration program, is executed.

[0036] Figure 3 shows an example of the functional configuration of the cyclic peptide molecule generation section. As shown in Figure 3, the cyclic peptide molecule generation section 112 has a Cα atom arrangement section 301, an addition section 302, and a structural relaxation section 303.

[0037] The Cα atom arrangement unit 301 identifies the Cα atoms, which are the atoms representing amino acids, in each of the acquired plurality of amino acid residue sequences, and arranges each of the identified plurality of Cα atoms at equal intervals on the circumference within the same plane. The example in FIG. 3 shows a state where eight amino acid residue sequences (Phe1, val2, Gly3, Thr5, Ser6, Phe7, Asp8) are acquired and input into the Cα atom arrangement unit 301. Note that arranging the Cα atoms at equal intervals on the circumference within the same plane is to enable the plurality of amino acid residue sequences (here, eight amino acid residue sequences) to take structures with high degrees of freedom relative to each other.

[0038] When the distance "a" between adjacent Cα atoms (for example, 3.84 Å) is input by the user, the Cα atom arrangement unit 301 calculates the radius of the circumference on which the Cα atoms are to be arranged based on the number "n" of the identified Cα atoms and the input distance "a" between the Cα atoms.

[0039] Also, the Cα atom arrangement unit 301 arranges the Cα atoms at equal intervals along the circumference of the calculated radius such that the distance between adjacent Cα atoms becomes "a". Here, the so-called equal intervals do not necessarily have to be exactly the same distance, and are synonymous with approximately equal intervals.

[0040] The addition unit 302 adds the main chain and side chain of the amino acid residue sequence to each Cα atom arranged on the circumference within the same plane.

[0041] The structure relaxation unit 303 sequentially relaxes the structure of each amino acid residue sequence generated by adding the main chain and side chain of the amino acid residue sequence to each Cα atom, thereby generating a model representing a cyclic peptide molecule having a plurality of amino acid residue sequences as the initial structure of the cyclic peptide molecule.

[0042] <Specific Example of Processing by Cα Atom Arrangement Unit> Next, a specific example of processing by the Cα atom arrangement unit 301 will be described. Figure 4 is a diagram showing a specific example of processing by the Cα atom arrangement unit. In the example in Figure 4, Cα atoms 401 to 408 are identified for each of the n=8 amino acid residue sequences and arranged at equal intervals on a circumference 400 in the same plane.

[0043] As shown in Figure 4, in the case of eight Cα atoms, the angle θ between the line from the center coordinate (0,0) of the circle with a circumference of 400 and the line from the adjacent Cα atom is 2π / n (=π / 4).

[0044] Furthermore, as shown in Figure 4, if the distance between adjacent Cα atoms is "a", the radius r of a circle with a circumference of 400 can be calculated using the following equation (1). (Equation 1) r = (a / 2) × [sin(π / n)] -1 Furthermore, the coordinates of each Cα atom 401-408 can be calculated using the following equation (2). (Formula 2) Coordinates = [rsin(n-1)θ x ,rcos(n-1)θ x ] In equation (2) above, r is the radius of a circle with a circumference of 400 calculated by equation (1), and θ x This can be calculated using the following formula (3). (Formula 3) θ x = x × 2π / n However, x is an integer between 1 and n.

[0045] <Specific examples of processing of added parts and structural relaxation parts> Next, specific examples of processing the added portion 302 and the structural relaxation portion 303 will be described. Figure 5 is a diagram showing specific examples of processing the added portion and the structural relaxation portion.

[0046] In Figure 5, reference numeral 510 indicates the addition result in which the addition unit 302 adds the main chain and side chains of the amino acid residue sequence to each Cα atom 401-408, which are arranged at equal intervals on the circumference in the same plane by the Cα atom arrangement unit 301. In the structural relaxation unit 303, once the addition result shown by reference numeral 510 is obtained from the addition unit 302, the structure after addition is relaxed so that the entropy decreases, thereby generating a model representing a cyclic peptide molecule as the initial structure of the cyclic peptide molecule.

[0047] On the other hand, symbol 520 shows the case where the initial structure of a cyclic peptide molecule is generated by a conventional method. The conventional method involves generating a linear peptide molecule by linking eight amino acid residue sequences in a linear fashion, and then cyclically forming the resulting linear peptide molecule by connecting the beginning and end of the linear peptide molecule.

[0048] As is clear from the comparison between symbols 510 and 520, in the case of the initial structure shown in symbol 510, the eight amino acid residue sequences are spaced further apart from each other compared to symbol 520, allowing for a structure with a high degree of freedom.

[0049] <Specific example of processing in the dihedral angle distribution calculation unit> Next, a specific example of the processing of the dihedral angle distribution calculation unit 113 will be described. As described above, the dihedral angle distribution calculation unit 113 obtains information indicating the dihedral angle of the backbone calculated during the stable structure search process from the server device 120, and outputs a dihedral angle distribution diagram by calculating the dihedral angle distribution based on the obtained information indicating the dihedral angle.

[0050] Here, we will briefly explain the dihedral angle of the backbone. Figure 6 is a diagram illustrating the dihedral angle of the backbone. In this embodiment, the dihedral angle distribution calculation unit 113 obtains (φ,ψ) as information indicating the dihedral angle from the server device 120. In Figure 6, reference numerals 601 and 602 indicate the i-th dihedral angle, which is the information indicating the i-th dihedral angle, obtained by the dihedral angle distribution calculation unit 113. i and ψ i This indicates that.

[0051] Next, we will explain the dihedral angle distribution diagram. Figures 7 and 8 are the first and second diagrams showing examples of dihedral angle distribution diagrams. In Figures 7 and 8, the horizontal axis represents φ [rad], which is information indicating the dihedral angle, and the vertical axis represents ψ [rad], which is information indicating the dihedral angle. Each plot in the diagram (Ramachandran plot) indicates that the information indicating the dihedral angle corresponding to each position was calculated during the search for a stable structure, and the difference in color of each plot represents the difference in the number of times it was searched.

[0052] Specifically, the closer to red the area is, the more times it has been explored, and the closer to blue the area is, the fewer times it has been explored. The white area indicates that it has not been explored even once.

[0053] Of these, Figure 7 is the dihedral angle distribution diagram of Ser6 when the initial structure was generated using the conventional method for eight amino acid residue sequences (Phe1, val2, Gly3, Thr5, Ser6, Phe7, Asp8) and then the stable structure was searched for. As mentioned above, the conventional method is a method of generating a linear peptide molecule by linearly linking eight amino acid residue sequences and then cyclizing the generated linear peptide molecule by linking the beginning and end.

[0054] On the other hand, Figure 8 shows the dihedral distribution of Ser6 when the initial structure is generated by the cyclic peptide molecule generation unit 112 for eight amino acid residue sequences (Phe1, val2, Gly3, Thr5, Ser6, Phe7, Asp8), and then the stable structure is searched for.

[0055] As can be seen from the comparison between Figure 7 and Figure 8, the dihedral angle distribution diagrams differ significantly when the initial structures are different. In other words, in the search for a stable structure by the server device 120, the search range differs significantly when the initial structures are different.

[0056] In this embodiment, we verify which search range is more appropriate by following the procedure below. • Of the eight amino acid residue sequences mentioned above (Phe1, val2, Gly3, Thr5, Ser6, Phe7, Asp8), 20 stable structures were obtained for Ser6 through nuclear magnetic resonance experiments. The dihedral angle information obtained for each of the 20 stable structures of Ser6 is plotted as ground truth data, overlaid on a dihedral angle distribution map. • Compare the search range indicated by each color plot in the dihedral angle distribution diagram with the degree of overlap between the white circles plotted as ground truth data, and verify whether the ground truth data is included within the search range.

[0057] In Figure 8, the 20 white circles represent information indicating the dihedral angles in 20 different stable structures obtained for Ser6. As shown in Figure 8, each white circle is located on the blue to light blue plot, and the stable structure search unit 121 will perform this search at least once during the search for a stable structure.

[0058] On the other hand, if the 20 white circles shown in Figure 8 were plotted directly onto the dihedral angle distribution diagram shown in Figure 7, some of the 20 white circles would be plotted within the white region. In other words, when the initial structure of a cyclic peptide molecule is generated using the conventional method, some of the 20 stable structures will not be explored even once during the search for stable structures.

[0059] In other words, when the initial structure of a cyclic peptide molecule is generated by operating the cyclic peptide molecule generation unit 112, it becomes possible to search for stable structures that would not be searched if the initial structure were generated by the conventional method. That is, when the initial structure of a cyclic peptide molecule is generated by operating the cyclic peptide molecule generation unit 112, the server device 120 can search for an appropriate search range compared to when the initial structure is generated by the conventional method.

[0060] <Flowchart of stable structure search process> Next, we will explain the overall flow of the stable structure search process. Figure 9 is a flowchart showing the flow of the stable structure search process.

[0061] In step S901, the terminal device 110 obtains multiple amino acid residue sequences. The terminal device 110 also obtains the distance a between adjacent Cα atoms.

[0062] In step S902, the terminal device 110 identifies the Cα atoms of each of the acquired amino acid residue sequences and places each Cα atom at equal intervals on a circle in the same plane calculated based on the distance a. The terminal device 110 also adds the main chain and side chain of the amino acid residue sequence to each of the placed Cα atoms and relaxes the structure after the addition to generate the initial structure of a cyclic peptide molecule.

[0063] In step S903, the terminal device 110 transmits information indicating the initial structure of the generated cyclic peptide molecule to the server device 120, thereby instructing it to search for a stable structure of the cyclic peptide molecule.

[0064] In step S904, the terminal device 110 obtains information from the server device 120 indicating the dihedral angle of the backbone calculated during the stable structure search process, and calculates the dihedral angle distribution based on the obtained dihedral angle information, thereby outputting a dihedral angle distribution diagram to the user.

[0065] In step S805, the terminal device 110 obtains information from the server device 120 indicating the stable structure of the searched cyclic peptide molecule and outputs it to the user.

[0066] As is clear from the above description, the terminal device 110 according to the first embodiment identifies the Cα atoms of each of the multiple amino acid residue sequences and arranges them at equal intervals on the circumference, and adds the main chain and side chains of the multiple amino acid residue sequences to each Cα atom arranged on the circumference. As a result, the terminal device 110 according to the first embodiment can generate the initial structure of a cyclic peptide molecule with a high degree of structural freedom for each of the multiple amino acid residue sequences.

[0067] Furthermore, the terminal device 110 according to the first embodiment transmits information indicating the initial structure of the generated cyclic peptide molecule to the server device 120, thereby instructing it to search for a stable structure of the cyclic peptide molecule.

[0068] As a result, according to the first embodiment, the search range when searching for a stable structure of a cyclic peptide molecule can be optimized.

[0069] [Second Embodiment] In the first embodiment described above, the stable structure search system 100 was described as being formed by a terminal device 110 and a server device 120. However, the stable structure search system 100 may be formed by devices other than the terminal device 110 and the server device 120 (i.e., three or more devices). Alternatively, the stable structure search system 100 may be formed by a device in which the terminal device 110 and the server device 120 are integrated (i.e., a single device).

[0070] Furthermore, in the first embodiment described above, the terminal device 110 was described as having an amino acid residue sequence acquisition unit 111 to a stable structure output unit 114, and the server device 120 was described as having a stable structure search unit 121. However, some functions of the terminal device 110 may be implemented in the server device 120. Alternatively, some functions of the server device 120 may be implemented in the terminal device 110.

[0071] Furthermore, in the first embodiment described above, an example was given in which eight amino acid residue sequences were used to generate the initial structure of a cyclic peptide molecule, but any number of amino acid residue sequences may be used to generate the initial structure of a cyclic peptide molecule. Also, in the first embodiment described above, a case was given in which a dihedral angle distribution plot was output for Ser6 among the eight amino acid residue sequences, but dihedral angle distribution plots for the remaining seven amino acid residue sequences may also be output.

[0072] Also, in the above first embodiment, although the details of the structural relaxation were not mentioned, in the structural relaxation unit 303, for example, the structural relaxation may be performed while fixing each Cα atom. Alternatively, in the structural relaxation unit 303, the structural relaxation may be performed including each Cα atom. Alternatively, the search for the stable structure may be started without performing the structural relaxation by the structural relaxation unit 303.

[0073] Note that in the disclosed technology, forms such as the following supplementary notes can be considered. (Supplementary Note 1) A generation unit that identifies the Cα atoms of each of a plurality of amino acid residues, arranges each of the identified plurality of Cα atoms on a circumference, and then adds the main chain and side chains of the plurality of amino acid residues to generate a model representing a cyclic peptide molecule; A search instruction unit that instructs a search unit to search for the stable structure of the cyclic peptide molecule using the generated model as the initial structure of the cyclic peptide molecule An initial structure generation device having the above. (Supplementary Note 2) The generation unit of the initial structure generation device according to Supplementary Note 1, which arranges each of the Cα atoms at equal intervals on the circumference. (Supplementary Note 3) The generation unit arranges n Cα atoms at positions with coordinates = [rsin(n - 1)θ x , rcos(n - 1)θ x (where r = (a / 2) × [sin(π / n)] -1 , θ x = x × 2π / n, x is an integer from 1 to n), the initial structure generation device according to Supplementary Note 1. (Supplementary Note 4) The initial structure generation device according to Supplementary Note 3, which has an acquisition unit that acquires the distance a between adjacent Cα atoms. (Supplementary Note 5) The generation unit of the initial structure generation device according to Supplementary Note 1, which generates a model representing the cyclic peptide molecule by relaxing the structure after addition. (Supplementary Note 6) The generating unit is an initial structure generating apparatus as described in Appendix 5, which relaxes the structure after addition while the Cα atom is fixed. (Note 7) The generating unit is an initial structure generating apparatus as described in Appendix 5, which relaxes the structure after addition, including the Cα atom. (Note 8) The initial structure generation apparatus according to Appendix 1, further comprising a calculation unit that calculates a dihedral angle distribution based on the dihedral angle of the backbone when a stable structure is searched based on the instructions of the search instruction unit. (Note 9) The calculation unit outputs the dihedral angle distribution in a color corresponding to the number of times a stable structure has been searched, as described in Appendix 8, for the initial structure generation apparatus. (Note 10) The initial structure generation apparatus described in Appendix 1, wherein the search unit searches for a stable structure using the generated model as the initial structure of the cyclic peptide molecule by an extended ensemble method. (Note 11) By identifying the Cα atoms of each of several amino acid residues, arranging each of the identified Cα atoms on a circumference, and then adding the main chain and side chains of the several amino acid residues, a model representing a cyclic peptide molecule is generated. The generated model is used as the initial structure of the cyclic peptide molecule, and the search unit is instructed to search for a stable structure of the cyclic peptide molecule. A method for generating an initial structure in which a computer performs processing. (Note 12) By identifying the Cα atoms of each of several amino acid residues, arranging each of the identified Cα atoms on a circumference, and then adding the main chain and side chains of the several amino acid residues, a model representing a cyclic peptide molecule is generated. The generated model is used as the initial structure of the cyclic peptide molecule, and the search unit is instructed to search for a stable structure of the cyclic peptide molecule. An initial structure generation program for enabling a computer to perform a process.

[0074] It should be noted that the present invention is not limited to the configurations shown in the above embodiments, including combinations with other elements. These aspects can be modified without departing from the spirit of the present invention and can be appropriately determined according to their application. [Explanation of symbols]

[0075] 100: Stable structure search system 110: Terminal device 111: Amino acid residue sequence acquisition section 112: Cyclic peptide molecule generation section 113: Dihedral angle distribution calculation part 114: Stabilized output section 120: Server device 121: Stable structure search section 301 :Cα atom arrangement part 302: Addition part 303: Structural relaxation part

Claims

1. A generation unit that identifies the Cα atom of each of several amino acid residues, arranges each of the identified Cα atoms along a circumference of a circle with a radius calculated based on the distance between adjacent Cα atoms, and then adds the main chain and side chains of the several amino acid residues to generate a model representing a cyclic peptide molecule. A search instruction unit instructs the search unit to search for a stable structure of the cyclic peptide molecule using the generated model as the initial structure of the cyclic peptide molecule. An initial structure generation apparatus having the following features.

2. The initial structure generating apparatus according to claim 1, wherein the generating unit arranges each of the Cα atoms at equal intervals on the circumference.

3. The generating unit arranges n Cα atoms so that the distance between adjacent Cα atoms is a, using the coordinate system = [rsin(n-1)θ]. ｘ , rcos(n-1)θ ｘ Place it at the position of ] (where r = (a / 2) × [sin(π / n)] －１ θ ｘ The initial structure generating apparatus according to claim 1, where x = x × 2π / n, x = an integer from 1 to n.

4. The initial structure generation apparatus according to claim 1, wherein the generation unit generates a model representing the cyclic peptide molecule by relaxing the structure after addition.

5. The initial structure generating apparatus according to claim 4, wherein the generating unit relaxes the structure after addition while the Cα atom is fixed.

6. The initial structure generating apparatus according to claim 4, wherein the generating unit relaxes the structure after addition, including the Cα atom.

7. The initial structure generation apparatus according to claim 1, further comprising a calculation unit that calculates a dihedral angle distribution based on the dihedral angle of the backbone when a stable structure is searched based on the instructions of the search instruction unit.

8. The initial structure generation apparatus according to claim 1, wherein the search unit searches for a stable structure using the generated model as the initial structure of the cyclic peptide molecule by an extended ensemble method.

9. A model representing a cyclic peptide molecule is generated by identifying the Cα atoms of each of several amino acid residues, arranging each of the identified Cα atoms along a circumference with a radius calculated based on a specified distance between adjacent Cα atoms, and then adding the main chain and side chains of the several amino acid residues. The generated model is used as the initial structure of the cyclic peptide molecule, and the search unit is instructed to search for a stable structure of the cyclic peptide molecule. A method for generating an initial structure in which a computer performs processing.

10. A model representing a cyclic peptide molecule is generated by identifying the Cα atoms of each of several amino acid residues, arranging each of the identified Cα atoms along a circumference with a radius calculated based on a specified distance between adjacent Cα atoms, and then adding the main chain and side chains of the several amino acid residues. The generated model is used as the initial structure of the cyclic peptide molecule, and the search unit is instructed to search for a stable structure of the cyclic peptide molecule. An initial structure generation program for enabling a computer to perform a process.

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