JP2010257297A - Device, program, and method for searching molecule stable structure - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To efficiently search a stable structure of molecules by arithmetic processing using a tunneling term. <P>SOLUTION: A molecule stable structure search device 400 for searching the stable structure of molecules includes an atom moving part 420 and a movement determination part 420 and an energy calculation part 430 and a search part 450. A movement determination part 420 determines whether or not the movement of the movement object atom is movement accompanied by the change of a dihedral angle. Then, when an energy calculation part 430 calculates the potential energy of molecules by using a tunnel term when the movement of the movement object atom is the movement accompanied by the change of the dihedral angle. A retrieval part 450 repeats the movement of the atom and the calculation of the potential energy, and searches the molecule structure to minimize the potential energy. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a molecular stable structure search device, a molecular stable structure search program, and a molecular stable structure search method. The molecular stable structure search device is a device that searches for a stable molecular structure with low potential energy. The molecular stable structure search program is a program that causes a computer to operate as such a molecular stable structure search apparatus. The molecular stable structure searching method is a method for searching for a stable molecular structure as described above.

  A molecule having a molecular structure in which a plurality of atoms are arranged has potential energy corresponding to the position of each atom constituting the molecule. The molecular structure becomes more stable as the potential energy of the molecule is lower.

  Conventionally, as a method for searching for a stable molecular structure, a method called a simulated annealing (SA) method is known (for example, see Patent Document 1). The SA method is a method of finding a stable structure in which the potential energy is finally minimized by gradually cooling the molecule while heating the molecule on the data and then changing the position of the atom to search for a structure having a low potential energy. .

  Here, when trying to move an atom, the movement of the atom is often hindered by an energy barrier of potential energy. In many cases, stable structures can be found by the movement of atoms beyond the energy barrier. In the SA method described above, in order to overcome such an energy barrier, it is necessary to heat the molecules at a high temperature exceeding the energy barrier. Since the SA method is a simulation, it is possible to set the heating temperature as high as possible. However, such heating at a high temperature may fundamentally change the molecular structure in the simulation, and may make it impossible to search for a stable structure for the molecule to be processed.

  Therefore, a method called a quantum annealing (QA) method has been proposed in which a problem related to the energy barrier as described above is avoided and a stable structure is searched. Unlike the SA method, the QA method apparently reduces the energy barrier by the tunnel effect, so that it is possible to search for a stable structure beyond the energy barrier.

  In the QA method, first, a stable structure is searched after a tunneling term that is a parameter indicating the degree of the tunnel effect is set to be large. In the QA method, an operation such as reducing the tunneling term according to a decrease in potential energy is performed, and finally a stable structure in which the potential energy is minimized is searched.

JP-A-9-106392

  However, in the above QA method, every time the molecular structure is changed in the simulation, it is necessary to repeat a complicated operation using the tunneling term, and it is difficult to efficiently search for a stable structure of the molecule. .

  In view of the above circumstances, an object of the present invention is to provide a molecular stable structure search apparatus, a molecular stable structure search program, and a molecular stable structure search method as described below. The molecular stable structure search apparatus is an apparatus that can efficiently search for a stable structure of a molecule. The molecular stable structure search program is a program that causes a computer to operate as such a molecular stable structure search apparatus. The molecular stable structure search method is a method that can efficiently search for a stable structure of a molecule.

  The basic form of the molecular stable structure search apparatus that achieves the above object includes an atom transfer unit, a transfer determination unit, an energy calculation unit, and a search unit.

  The atom moving unit is configured such that, for each molecule in which a plurality of atoms are arranged at each coordinate point and the potential energy changes with the coordinate movement of the atom, the coordinates of the movement target atom among the atoms constituting the molecule are displayed on the data. It is to be moved.

  The movement determination unit determines whether or not the current movement of the movement target atom in the atomic movement unit is a first type of movement in which movement of the movement target atom is hindered by an energy barrier of potential energy. It is determined whether the movement is the second type of removal.

  Depending on whether the movement of the movement target atom is the first type movement or the second type movement, the energy calculation unit respectively has the following first potential function and second Based on the potential function, the potential energy of the molecule is calculated. The first potential function is a function including a tunneling term that depends on coordinate points of a plurality of atoms constituting the molecule and reduces the energy barrier. The second potential function is a function obtained by removing the tunneling term from the first potential function.

  The search unit searches for coordinate points of a plurality of atoms constituting the molecule where the potential energy of the molecule is minimized by the following process. That is, the search unit alternately repeats the movement of the atom to be moved by the atom moving unit and the calculation of the potential energy of the molecule by the energy calculating unit. Then, the search unit reduces the repetition including the disappearance of the effect of the tunneling term of the first potential function according to the decrease of the calculated potential energy in the case of the first type of movement. Run while.

  In addition, a basic form of a molecular stable structure search program that achieves the above object is executed in a computer, and on the computer, the atomic transfer unit, the transfer determination unit, the energy calculation unit, the search unit, Is to build.

  In addition, the basic form of the molecular stable structure search method that achieves the above object includes an atomic transfer process, a transfer determination process, an energy calculation process, and a search process.

  In the atomic movement process, for each molecule in which multiple atoms are arranged at each coordinate point and the potential energy changes as the atoms move, the coordinates of the atoms to be moved among the atoms constituting the molecule are displayed on the data. It is a process of moving.

  In the movement determination process, the current movement of the movement target atom in the above-described atomic movement process is the first type of movement in which the movement of the movement target atom is hindered by the energy barrier of the potential energy. This is a process of determining whether the movement is the second type of movement.

  The energy calculation process is a process of calculating the potential energy of the molecule depending on whether the movement of the movement target atom is the first type movement or the second type movement. In this energy calculation process, depending on whether the movement is the first type movement or the second type movement, the potential energy is changed to the following first potential function and second potential, respectively. Calculated based on the function. The first potential function is a function including a tunneling term that depends on coordinate points of a plurality of atoms constituting the molecule and reduces the energy barrier. The second potential function is a function obtained by removing the tunneling term from the first potential function.

  The search process is a process of searching for coordinate points of a plurality of atoms constituting the molecule where the potential energy of the molecule is minimized by the following process. That is, in this search process, the movement of the atom to be moved by the atomic movement process and the calculation of the potential energy of the molecule by the energy calculation process are alternately repeated. In this search process, the repetition reduces the influence of the tunneling term of the first potential function including the disappearance of the influence according to the calculated potential energy drop in the case of the first type of movement. While being executed.

  According to this case, a stable structure of a molecule can be searched efficiently.

It is a figure which shows the computer which operate | moves as one specific embodiment of the molecular stable structure search apparatus mentioned above about the basic form. It is a hardware block diagram of the computer shown in FIG. It is a conceptual diagram which shows CD-ROM with which specific embodiment of the molecular stable structure search program which demonstrated the basic form was memorize | stored. It is a block diagram which shows specific embodiment of the molecular stable structure search apparatus demonstrated about the basic form. It is a figure which shows the process from step S101 to step S113 in the flowchart which shows the flow of the molecular stable structure search process performed with the molecular stable structure search apparatus of FIG. It is a figure which shows the process after step S114 in the flowchart which shows the flow of the molecular stable structure search process performed with the molecular stable structure search apparatus of FIG. It is a schematic diagram which shows the movement of an atom accompanying the change of a dihedral angle. It is a figure which shows the process of step S200 of FIG. 5 in detail. It is a figure which shows an example of a simple molecular structure. It is a figure which shows typically a mode that a stable structure is searched by the molecular stable structure search process with respect to the molecule | numerator M1 of FIG. In 2nd Embodiment, it is a flowchart which shows the flow of a process which calculates energy U 'after a movement, when it is a movement accompanied by the change of a dihedral angle. It is a figure explaining the proper use of two types of tunneling terms.

  Hereinafter, specific embodiments of the molecular stable structure searching apparatus, the molecular stable structure searching program, and the molecular stable structure searching method described above for the basic form will be described with reference to the drawings.

  First, the first embodiment will be described.

  FIG. 1 is a diagram illustrating a computer that operates as a specific embodiment of the molecular stable structure search apparatus described above for the basic mode. FIG. 2 is a hardware configuration diagram of the computer shown in FIG.

  The computer 100 includes a main body 110, an image display device 120, a keyboard 130, and a mouse 140.

  The main body 110 is a device that incorporates a CPU 111 and a hard disk device (HDD) 113, which will be described later, and executes various processes. Further, the main body 110 has a CD-ROM loading slot 110A into which the CD-ROM 200 is loaded. The image display device 120 is a device that displays an image on the monitor 121 in accordance with an instruction from the main body 110. The keyboard 130 is for inputting user instructions and character information to the computer 100. The mouse 140 designates an arbitrary position on the monitor 121 and inputs an instruction corresponding to the position to the computer 100.

  As shown in FIG. 2, a CPU 111, a main memory 112, an HDD 113, a CD-ROM drive 114, and an I / O interface 115 are built in the main body 110.

  The CPU 111 executes various programs. The main memory 112 is a memory in which a program stored in the HDD 113 is read and expanded for execution by the CPU 111. The HDD 113 is a memory that stores various programs and data. The CD-ROM drive 114 accesses the CD-ROM 200 loaded from the CD-ROM loading slot 110A. The I / O interface 115 is an interface for the computer 100 to exchange data with an external device. These various elements, the image display device 120, the keyboard 130, and the mouse 140 also shown in FIG. 1 are connected to each other via a bus 116.

  When a later-described molecular stable structure search program is installed in the computer 100 described above, the computer 100 operates as a molecular stable structure search apparatus.

  FIG. 3 is a conceptual diagram showing a CD-ROM storing a specific embodiment of the molecular stable structure search program described for the basic mode.

  The molecular stable structure search program 300 stored in the CD-ROM 200 and causing the computer 100 to operate as a molecular stable structure search device corresponds to a specific embodiment of the molecular stable structure search program described above for the basic mode. The molecular stable structure search program 300 includes an initial structure data input unit 310, an atom transfer unit 320, a movement determination unit 330, an energy calculation unit 340, a search unit 350, and a search result storage / display unit 360. . Details of each element of the molecular stable structure search program 300 will be described later.

  FIG. 4 is a block diagram showing a specific embodiment of the molecular stable structure search apparatus described for the basic mode.

  The molecular stable structure search apparatus 400 shown in FIG. 4 is configured by installing and executing the molecular stable structure search program 300 of FIG. 3 in the computer 100 of FIG. The molecular stable structure searching apparatus 400 includes an initial structure data input unit 410, an atom transfer unit 420, a movement determination unit 430, an energy calculation unit 440, a search unit 450, and a search result storage / display unit 460. .

  When the molecular stable structure search program 300 of FIG. 3 is installed in the computer 100 of FIG. 1, each element of the molecular stable structure search program 300 constructs each element of the molecular stable structure search apparatus 400. That is, the initial structure data input unit 310 of the molecular stable structure search program 300 constructs the initial structure data input unit 410 of the molecular stable structure search device 400. Further, the atom transfer unit 320 of the molecular stable structure search program 300 constructs the atom transfer unit 420 of the molecule stable structure search apparatus 400. Further, the movement determination unit 330 of the molecular stable structure search program 300 constructs the movement determination unit 430 of the molecular stable structure search apparatus 400. In addition, the energy calculation unit 340 of the molecular stable structure search program 300 constructs the energy calculation unit 440 of the molecular stable structure search device 400. Further, the search unit 350 of the molecular stable structure search program 300 constructs the search unit 450 of the molecular stable structure search apparatus 400. Then, the search result storage / display unit 360 of the molecular stable structure search program 300 constructs the search result storage / display unit 460 of the molecular stable structure search device 400.

  Here, each element of the molecular stable structure searching apparatus 400 is configured by a combination of computer hardware and an OS or application program executed on the computer. On the other hand, each element of the molecular stable structure search program 300 in FIG. 3 is configured only by an application program.

  The atom transfer unit 420 of the present embodiment corresponds to an example of the atom transfer unit in the basic mode described above. In addition, the movement determination unit 430 corresponds to an example of the movement determination unit in the basic form described above. The energy calculation unit 440 corresponds to an example of the energy calculation unit in the basic form described above. The search unit 450 corresponds to an example of the search unit in the basic form described above.

  Hereinafter, the details of each element of the molecular stable structure searching apparatus 400 of FIG. 4 will be described along the flow of the molecular stable structure searching process executed by the molecular stable structure searching apparatus 400. In addition, by describing each element of the molecular stable structure searching apparatus 400, each element of the molecular stable structure searching program 300 shown in FIG. 3 will also be described.

  FIG. 5 is a diagram showing the process from step S101 to step S113 in the flowchart showing the flow of the molecular stable structure search process executed by the molecular stable structure search apparatus of FIG. FIG. 6 is a diagram showing the processing after step S114 in the flowchart showing the flow of the molecular stable structure searching process executed by the molecular stable structure searching apparatus of FIG. The molecular stable structure searching process shown in the flowcharts of FIGS. 5 and 6 corresponds to a specific embodiment of the molecular stable structure searching method described above for the basic mode.

  The molecular stable structure search process shown in the flowcharts of FIGS. 5 and 6 is a process of searching for a molecular structure (stable structure) in which the potential energy of the molecule to be processed is the lowest while moving each atom by Monte Carlo simulation.

  This molecular stable structure search process starts when the start of the molecular stable structure search process is instructed by a user operation on a predetermined operation screen. When the process is started, the initial structure data input unit 410 inputs initial structure data representing an initial structure in which each atom is arranged at a predetermined initial position to the molecule stable structure searching device 400 by a user operation. An input is accepted (step S101). In the present embodiment, this initial structure data defines the initial position of each atom constituting the molecule to be processed by coordinates in a predetermined virtual three-dimensional space. The initial structure data is preliminarily constructed by a known design support tool or the like that constructs a molecular structure in a virtual three-dimensional space.

  Next, based on the initial structure data input in step S101, the energy calculation unit 440 calculates the potential energy possessed by the molecule corresponding to the initial structure data (step S102).

  The potential energy of a molecule is the sum of potential energies possessed by each of a plurality of atoms constituting the molecule. In addition, the potential energy of each atom includes an interaction with an adjacent atom. When the potential energy of each atom is Ei (Xi, Yi, Zi), the potential energy U of the molecule is expressed by the following equation (1). Here, the letter “i” is an identification number corresponding to each of a plurality of primitives constituting the molecule. “(Xi, Yi, Zi)” is the position coordinate of the atom with the identification number “i” in the virtual three-dimensional space.

  Note that the calculation of the potential energy Ei (Xi, Yi, Zi) of each atom is well-known and will not be described here.

  When the potential energy of the molecule is calculated in step S102, the energy calculation unit 440 passes the calculation result to the search unit 450.

  Next, the atom moving unit 420 selects a moving target atom by Monte Carlo simulation from a plurality of primitives constituting the molecule with a predetermined selection probability (step S103). In addition, each of a plurality of primitives constituting a molecule can move according to the degree of freedom of each atom resulting from the molecular structure. There are as many movable directions in which each atom can move according to the degree of freedom of the atom. In step S103, the atom moving unit 420 selects a moving target atom and selects the moving direction of the atom from the moving directions existing for the atom with a predetermined selection probability.

  When the movement target atom and the movement direction are determined, the atom moving unit 420 moves the atom in the movement direction by a predetermined distance dR (step S104).

  The process in which the process in step S103 and the process in step S104 are combined corresponds to an example of the atomic transfer process in the basic mode.

  Next, the movement determination unit 430 determines whether or not the movement of atoms in step S104 is a movement accompanied by a change in dihedral angle described below (step S105). The process in step S105 corresponds to an example of a movement determination process in the basic form described above.

  FIG. 7 is a schematic diagram showing the movement of atoms with a change in dihedral angle.

  In FIG. 7, as an example, in the molecular structure in which the first to fourth atoms A1,..., A4 are connected to each other by the first to third bond axes B1, B2, and B3, A state in which A2 is moved with a change in dihedral angle is shown. And the molecular structure before the movement is shown in part (A) of FIG. Moreover, the molecular structure after movement is shown in part (B) of FIG.

  In the example of FIG. 7, the surface formed by the first atom A1, the second atom A2, and the third atom A3, and the first atom A1, the third atom A3, and the fourth atom A4 are formed. The dihedral angle formed by the forming surface is changed from “θ1” to “θ2” by the movement of the second atom A2.

  In protein molecules, drug candidate compounds, etc., the movement of an atom accompanied by a change in dihedral angle as shown in FIG. 7 has a large interaction with other atoms, and the molecular potential energy has a complex amplitude. Often causes a large increase or decrease. On the other hand, a movement that extends or shortens the distance between atoms has a small interaction with other atoms, and the increase or decrease in the potential energy of the molecule accompanying this movement is often small in amplitude.

  In step S105 of FIG. 5, whether or not the atom movement in step S104 is a movement accompanied by a change in dihedral angle, which may cause a complicated increase and decrease in amplitude of the potential energy of the molecule to be processed. Is determined.

  First, when the movement determination unit 440 determines that the movement is not accompanied by a change in dihedral angle (NO determination in step S105), the energy calculation unit 440 executes the following calculation process (step S106). In step S106, the energy calculation unit 440 calculates the potential energy (post-transfer energy) U ′ of the molecule corresponding to the structure data reflecting the post-transfer atomic position by the above formula (1).

  On the other hand, when the movement determination unit 440 determines that the movement is accompanied by a change in dihedral angle (YES determination in step S105), the energy calculation unit 440 converts the post-movement energy U ′ into a series of processes described below. (Step S200).

  FIG. 8 is a diagram showing in detail the process of step S200 of FIG.

  As shown in FIG. 8, the energy calculation unit 440 first calculates the potential energy EA before movement and the potential energy EB after movement in the above step S104 for the movement target atom (step S201). This calculation is performed by a known method, similarly to the calculation of the potential energy Ei (Xi, Yi, Zi) of the atoms in the processing of step S102 or step S106.

  Next, the energy calculation unit 440 creates a Hamiltonian (tunneling term introducing Hamiltonian) H ′ using a tunneling term Q described below, and diagonalizes the tunneling term introducing Hamiltonian H ′ (step S202).

  In the process of step S202, the energy calculation unit 440 first creates a 2-by-2 diagonal matrix having the above-mentioned potential energy EA, EB before and after movement as diagonal terms. Further, by replacing the term “0” in the diagonal matrix with a tunneling term Q having a predetermined value, a 2-by-2 tunneling term introduced Hamiltonian H ′ shown in FIG. 8 is obtained. Then, the energy calculation unit 440 transforms the tunneling term introduced Hamiltonian H ′ into a form represented by the following equation (2) by diagonalizing the two-row and two-column tunneling term introduced Hamiltonian H ′.

  The upper left term of the diagonal terms in the tunneling term introduced Hamiltonian H ′ represented by the equation (2) is the potential energy EA ′ before the movement, in which the tunneling term Q is introduced for the atom to be moved. Further, the lower right term of the diagonal terms is the potential energy EB ′ after the movement in which the tunneling term Q is introduced.

  When the energy calculation unit 440 executes diagonalization of the tunneling term introduced Hamiltonian H ′ as described above, the energy calculation unit 440 performs a matrix operation for extracting the lower right term from the diagonalized tunneling term introduced Hamiltonian H ′ (Step S1). S203). By the processing in step S203, the energy calculation unit 440 obtains the potential energy EB ′ after the movement in which the tunneling term Q is introduced for the movement target atom.

  Next, the energy calculation unit 440 calculates the sum U1 of potential energies of atoms other than the movement target atom for the molecule to be processed (step S204). The calculation in step S204 is performed by a process equivalent to step S102 described above. However, the interaction based on the potential energy EB ′ after the movement, in which the tunneling term Q is introduced, is applied to the interaction from the movement target atom with respect to the atom adjacent to the movement target atom.

  Here, when the potential energy of the transfer target atom increases, the interaction from the transfer target atom with respect to the atom adjacent to the transfer target atom also increases. At this time, from the above equation (2), it can be seen that the potential energy EB ′ after movement in which the tunneling term Q is introduced is lower than the potential energy EB after movement in which the tunneling term Q is not introduced. That is, even if the potential energy of the movement target atom increases due to the movement of the movement target atom, the increase of the potential energy of the movement target atom is reduced by the introduction of the tunneling term Q as described above. Thereby, the interaction from the moving target atom with respect to the atom adjacent to the moving target atom is also reduced by the introduction of the tunneling term Q. As a result, the increment of the total sum U1 of potential energies of atoms other than the transfer target atom is reduced.

  Next, the energy calculation unit 440 adds the post-migration potential energy EB ′ obtained in step S203 for the migration target atom to the total potential energy U1 of atoms other than the migration target atom calculated in step S204. (Step S205). By this addition, the post-migration energy U ′ into which the tunneling term Q has been introduced is obtained for the molecule corresponding to the structural data after the migration.

  Here, as described above, the potential energy EB ′ after the movement obtained in step S <b> 203 for the atom to be moved is lowered by the introduction of the tunneling term Q. And about the sum total U1 of the potential energy of atoms other than a movement object atom, an additional part is reduced by introduction | transduction of the tunneling term Q. FIG. As a result, the increased energy is also reduced for the post-movement energy U ′ obtained in step S205. This means that the amplitude of increase / decrease in potential energy caused by the movement of the atom to be moved accompanying the change of the dihedral angle is relaxed, and thus the energy barrier caused by such movement is reduced.

  A combination of mathematical expressions used in the series of processes in step S200 described above corresponds to an example of the first potential function referred to in the basic form. In addition, the expression (1) used in the process of step S106 in FIG. 5 corresponds to an example of the second potential function described in the basic form.

  The post-movement energy U ′ obtained by the process of step S106 in FIG. 5 or the series of processes of step S200 described above is passed from the energy calculation unit 440 to the search unit 450.

  The process that combines the process of step S106 and the process of step S200 corresponds to an example of the energy calculation process in the basic mode described above.

  When the post-movement energy U ′ is received, the search unit 450 obtains the differential energy dU by subtracting the potential energy U of the molecule before the movement from the post-movement energy U ′ (step S <b> 107). Then, the search unit 450 determines whether or not the difference energy dU has a negative value, that is, whether or not the energy U ′ after movement is smaller than the potential energy U before movement (step S108). ).

  When the differential energy dU is a negative value, it means that the molecule after the transfer target atom has moved has shifted to a stable state in which the potential energy is lower than that before the transfer. For this reason, when the differential energy dU is a negative value (YES determination in step S108), the search unit 450 employs a position after movement that stabilizes the entire molecule as the position of the movement target atom. (Step S109). Then, the search unit 450 employs the post-movement energy U ′ obtained in Step S106 or Step S200 as the potential energy U of the molecule to be processed (Step S110).

  On the other hand, when the differential energy dU is a value of “0” or more, it means that the molecule after the atom has moved has shifted to an unstable state with higher potential energy than before the movement. . However, even if the movement of the predetermined distance dR in step S104 shifts to an unstable state, there is still a possibility of shifting to a stable state where the potential energy is low when the movement target atom is further moved. .

  Therefore, when the difference energy dU is a value equal to or greater than “0” (NO determination in step S108), the search unit 450 firstly uses the difference energy dU as a parameter as a probability function EXP (−dU / B). Is substituted with the differential energy dU obtained in step S107. Then, search unit 450 compares the substitution result with a uniform random number between “0” and “1.0” (step S111).

  If the above substitution result is larger than the uniform random number (YES determination in step S111), the process proceeds to step S109, where the search unit 450 adopts the position of the atom after movement and the energy U ′ after movement. Is adopted.

  On the other hand, when the above substitution result is equal to or less than the uniform random number (NO determination in step S111), the search unit 450 adopts the position of the atom before the movement (step S112) and the potential energy U before the movement. (Step S113).

  As described above, regarding the movement of the atom to be moved, when the position of the atom after the movement, that is, the determination of the molecular structure in the molecule after the movement and the potential energy U before the movement is completed, the process is the step of FIG. Proceed to S114.

  In step S114, the search unit 450 determines whether or not the Monte Carlo simulation for the molecule to be processed has been completed (step S114). In this embodiment, this determination is made as to whether or not the movement of atoms for a predetermined step in all directions that can move in the molecule to be processed has been performed for all atoms that constitute the molecule to be processed. It is done by judging.

  When it is determined that it has not been completed (NO determination in step S114), the search unit 450 determines whether or not the potential energy U of the molecule determined at this time is smaller than a predetermined threshold value. (Step S115).

  If the potential energy U of the molecule is equal to or greater than the threshold value (NO determination at step S114), the processing after step S103 in FIG. 5 is executed again. In the present embodiment, such re-execution of the process is performed by an instruction from the search unit 450 to the atom transfer unit 420 and the energy calculation unit 440.

  On the other hand, when the potential energy U of the molecule is smaller than the threshold value (YES determination in step S114), first, the search unit 450 sets the tunneling term Q to “0” (step S116). And the process after step S103 of FIG. 5 is performed again according to the instruction | indication of the search part 450. FIG. When the process of step S116 is performed, the same process as the process of step S106 is executed in step S200 described above.

  The processing from step S103 to step S116 described above is repeated until the search unit 450 determines that the Monte Carlo simulation has been completed (YES determination in step S114). When the Monte Carlo simulation is completed, the search unit 450 passes the structure data representing the molecular structure finally obtained for the molecule to be processed to the search result storage / display unit 460.

  The processes from step S107 to step S116 described above correspond to an example of the search process in the basic form described above.

  When the search result storage / display unit 460 receives the final structure data, the search result storage / display unit 460 stores the structure data in a predetermined memory and displays an image of the molecule corresponding to the structure data on the monitor 121 of FIG. With the display of the structure data, the molecular stable structure search process shown in the flowcharts of FIGS. 5 and 6 is completed.

  Hereinafter, the fact that the stable structure of a molecule can be efficiently searched by the molecular stable structure searching process described so far will be described by taking a simple molecular structure as an example.

  FIG. 9 is a diagram showing an example of a simple molecular structure.

  FIG. 9 shows a molecule M1 in which nine atoms A1,..., A9 to which a series of identification numbers i are assigned are bonded in a zigzag manner. Furthermore, in order to simplify the explanation, in the molecule M1 in FIG. 9, only the atom A3 having the identification number i of “3” can move, and the degree of freedom is “1”, and the arrow D1 in the figure. It can be moved only in the direction indicated by. Furthermore, it is assumed that the moving direction indicated by the arrow D1 is a movement accompanied by a change in dihedral angle.

  Further, in the atom A3 having the identification number i of “3”, the position drawn with a solid line in FIG. 9 is the initial position P1. Then, it is assumed that there is a stable position P2 at which the potential energy of the molecule M1 is lowest at the position depicted by the dotted line in FIG. 9 on the movement direction indicated by the arrow D1.

  When the molecular stable structure search process of FIGS. 5 and 6 is performed on the molecule M1 of FIG. 9, the stable structure in which the atom A3 having the identification number i of “3” is arranged at the stable position P2 is as follows. It will be searched as described in (1).

  FIG. 10 is a diagram schematically showing how a stable structure is searched for by the molecular stable structure search process for the molecule M1 of FIG.

  Part (A) of FIG. 10 shows the change in potential energy U of the molecule M1 when the atom A3 having the identification number i of “3” is continuously moved in the movement direction indicated by the arrow D1 in FIG. The first curve L1 shown is shown together with the atom A3 arranged at the initial position P1. Further, in Part (B) of FIG. 10, the first curve L1 is shown together with the atom A3 arranged at the stable position P2.

  As described above, the movement of atoms accompanied by the change of the dihedral angle often causes a large increase or decrease in the amplitude of the complex potential energy of the molecule. In part (A) and part (B) of FIG. 10, such a complex increase / decrease in amplitude of potential energy is indicated by a first curve L1.

  Here, in the change of the potential energy indicated by the first curve L1, there are a plurality of metastable states in which the potential energy is low, in addition to the ground state in which the potential energy is the lowest. ing. And the metastable states are separated by an energy barrier. At this time, it is assumed that the initial position P1 of the movement target atom A3 corresponds to the metastable state as shown in part (A) of FIG. On the other hand, the stable position P2 is a position corresponding to a ground state different from the initial position P1 as shown in part (B) of FIG.

  As described above, in the molecular stable structure search process of FIGS. 5 and 6, the post-movement energy U ′ after moving the atoms by the predetermined distance dR is basically smaller than the potential energy U before the movement. If so, the position of the atom after the movement is adopted. Further, when the energy U ′ after movement is equal to or higher than the potential energy U before movement, the substitution result obtained by substituting the difference energy dU into the probability function EXP (−dU / B) is larger than the uniform random number. The position of the atom after moving is adopted.

  Here, it is assumed that the atom A3 before the movement is arranged at a position corresponding to any metastable state (for example, the initial position P1) as in part (A) of FIG.

  Also, unlike the present embodiment, the energy U ′ after movement is not used in the above tunneling term for the movement of atoms accompanied by a change in dihedral angle, which often causes a large increase / decrease in the amplitude of the potential energy. Let's consider the case of calculation.

  In this case, the post-movement energy U ′ after the movement of the atom A <b> 3 is always greater than the potential energy U before the movement due to the energy barrier. Further, as described above, the amplitude of increase / decrease is large in the change in potential energy accompanying the movement of atoms performed with the change in dihedral angle. Therefore, the difference energy dU before and after the movement of the atoms increases, and the substitution result obtained by substituting the difference energy dU into the probability function EXP (−dU / B) decreases. As a result, the position of the atom after movement becomes difficult to be adopted, and it becomes difficult to find a stable structure in which the atom is arranged at the stable position P2.

  On the other hand, in this embodiment, for the movement of atoms accompanied by such a change in dihedral angle, the amplitude of increase / decrease in potential energy is apparently relaxed by using the tunneling term as described above. To calculate post-movement energy U ′.

  Part (C) of FIG. 10 shows a second curve L2 showing a change in which the amplitude of increase / decrease of the potential energy U of the molecule M1 is relaxed.

  In such a calculation in the present embodiment, the energy barrier is apparently low. Therefore, the increment after the movement of the potential energy U when the atom A3 is moved from the position corresponding to a certain metastable state becomes small. That is, the difference energy dU before and after the movement of the atom A3 decreases, and the substitution result obtained by substituting the difference energy dU into the probability function EXP (−dU / B) increases. As a result, the position of the atom A3 after the movement is easily adopted, and the energy barrier that prevents the movement to the stable position P2 is easily exceeded. In this embodiment, when the potential energy U of the molecule is lowered to some extent, it is considered that the energy barrier corresponding to the peripheral position of the stable position P2 is exceeded, and the tunneling term is set to “0”. This prevents the atom A3 reaching the periphery of the stable position P2 from passing through the stable position P2. According to the present embodiment, a stable structure in which the atom A3 is arranged at the stable position P2 can be reliably found by the arithmetic processing using such a tunneling term.

  Further, in the present embodiment, the complicated calculation process as described above using the tunneling term is performed only for the movement of atoms accompanied by the change of the dihedral angle. As a result, it is efficient because execution of such complicated arithmetic processing is minimized. That is, according to this embodiment, a stable structure of a molecule can be searched efficiently.

  As described above, in protein molecules, drug candidate compound molecules, etc., the movement of an atom accompanied by a change in dihedral angle has a large interaction with other atoms, and the potential energy of the molecule is complicated and has an amplitude. Often causes a large increase or decrease. For this reason, the fact that the processing target of the arithmetic processing using the tunneling term is the movement of the atom accompanied by the change of the dihedral angle is very effective for the search for the stable structure of the molecule as described above.

  This means that the application modes described below are preferable to the basic mode described above. In this application mode, when the movement of the movement target atom is a movement accompanied by a change in dihedral angle in the molecular structure of the molecule, the movement determination unit determines the movement of the movement target atom as the first type movement. It is determined to be.

  The movement determination unit 430 of the present embodiment also corresponds to an example of a movement determination unit in this application mode.

  In the present embodiment, as described above, the tunneling term is set to “0” when the potential energy U of the molecule is lowered to some extent. In general QA methods, a method of gradually lowering the tunneling term as the potential energy decreases is often employed. On the other hand, in the present embodiment, the speed of the stable structure search is increased by maintaining a tunneling term having a certain size until the molecular structure approaches the stable structure.

  This means that the application modes described below are preferable to the basic mode described above. In this application mode, the search unit eliminates the influence of the tunneling term of the first potential function when a potential energy smaller than a predetermined threshold is calculated as the potential energy of the molecule. Yes.

  The search unit 450 of the present embodiment also corresponds to an example of a search unit in this application mode.

  Next, a second embodiment will be described.

  The second embodiment is different from the first embodiment described above in the process of calculating the post-movement energy U ′ when the movement of the movement target atom is a movement accompanied by a change in dihedral angle.

  On the other hand, the second embodiment is equivalent to the molecular stable structure search program 300 and the molecular stable structure search apparatus 400 of the first embodiment described above with respect to the basic configuration of the molecular stable structure search program and the molecular stable structure search apparatus. It is. Further, the second embodiment is also equivalent to the molecular stable structure search process in the first embodiment described above with respect to the basic flow of the molecular stable structure search process.

  Therefore, in the following, illustration and overlapping description of the basic flow of the molecular stable structure search program, molecular stable structure search device, and molecular stable structure search process of the second embodiment will be omitted, and The explanation will focus on the above differences. In the following, FIG. 4 showing the molecular stable structure searching device 400 of the first embodiment and FIG. 5 showing the basic flow of the molecular stable structure searching process of the first embodiment will be referred to as appropriate.

  FIG. 11 is a flowchart showing a flow of processing for calculating post-movement energy U ′ when the movement is accompanied by a change in dihedral angle in the second embodiment.

  In FIG. 11, steps equivalent to those in the flowchart of FIG. 8 showing the flow of such processing in the first embodiment are denoted by the same reference numerals as in FIG. In the following, redundant description of this equivalent step is omitted.

  In the present embodiment, when the energy calculation unit 440 calculates the post-movement energy U ′ for the movement accompanied by the change of the dihedral angle, the first and second types of tunneling terms having different sizes are appropriately selected. Use properly. That is, the energy calculation unit 440 has two types of tunneling terms having different values corresponding to each atom group when the molecule to be processed is divided into two, and the tunneling term corresponding to the atom group to which the movement target atom belongs. Use to calculate.

  In the flowchart of FIG. 11, after the process of step S201 described above, the energy calculation unit 440 first includes the movement target atom belonging to a predetermined atomic group that is one of the two atomic groups. It is determined whether or not (step S301). When the transfer target atom does not belong to the predetermined atom group and belongs to the other atom group (NO determination in step S301), the first tunneling term Q1 is adopted (step S302). On the other hand, when the movement target atom belongs to the predetermined atom group (YES determination in step S301), the second tunneling term Q2 having a value larger than the first tunneling term Q1 is adopted (step S303). ).

  Then, using the tunneling term adopted in step S302 or step S303, the subsequent processing from step S202 to step S205 is executed, and the post-movement energy U 'is obtained.

  In the present embodiment, as described above, using two types of tunneling terms depending on which atom group in the molecule the moving target atom belongs to has the meaning described below.

  FIG. 12 is a diagram for explaining the proper use of two types of tunneling terms.

  FIG. 12 shows a molecule M2 in which 13 atoms A1,..., A13 from 1 to 13 are bonded in a zigzag manner. Further, FIG. 12 shows first and second atomic groups M2_1 and M2_2 that bisect the molecule M2. The first tunneling term Q1 is used for the atoms in the first atomic group M2_1, for example, the third atom A3. As with the ninth atom A9, for the atoms in the second atomic group M2_2, the second tunneling term Q2 having a value larger than that of the first tunneling term Q1 is used.

  Here, in a protein molecule, a drug candidate compound molecule, or the like, there may be a portion where the amplitude of increase / decrease in potential energy accompanying the movement of atoms is significantly larger than other atoms in the molecule. Therefore, in the present embodiment, the tunneling term Q2 having a relatively large value is used for atoms in an atomic group (in this example, the second atomic group M2_2) in which the amplitude of increase / decrease in potential energy is particularly large. It has become. As a result, the amplitude of the increase / decrease of the potential energy accompanying the movement of the atoms is sufficiently relaxed even for the atom at the location where the increase / decrease amplitude of the potential energy increases.

  On the other hand, if the amplitude of increase / decrease in potential energy is too relaxed, a clear difference in potential energy becomes too small before and after movement, and it becomes difficult to search for a stable structure. However, in the present embodiment, the use of the tunneling term Q2 having a relatively large value as described above is limited to the atomic group in which the amplitude of increase / decrease in the potential energy is particularly large, thereby avoiding the above problem. It is supposed to be done.

  Note that which atomic group in the molecule has a particularly large amplitude of increase / decrease in potential energy can be empirically grasped through experiments using actual molecules. When the initial structure data is input, information indicating each atomic group when the molecular structure is bisected and correspondence information that associates each atomic group with a tunneling term are input together with the initial structure data. Then, based on each input information, the proper use of the tunneling terms as described above is executed.

  In the present embodiment, by properly using the tunneling terms, a search process for a good stable structure in which the amplitude of increase / decrease in potential energy is appropriately relaxed for each primitive constituting the molecule is executed.

  This means that the application modes described below are preferable to the basic mode described above. In this application mode, the energy calculation unit has a plurality of tunneling terms having different values associated with each atom group when the molecule is divided into a plurality of atom groups. The energy calculation unit calculates the potential energy of the molecule using the tunneling term corresponding to the atomic group to which the transfer target atom belongs when the transfer of the transfer target atom is the first type transfer. To do.

  The energy calculation unit 440 of the present embodiment corresponds to an example of the energy calculation unit in this application mode.

  In the above description, as a specific embodiment of the molecular stable structure searching apparatus described above with respect to the basic form, the form in which the stable structure is searched while moving the atoms one by one by Monte Carlo simulation and changing the molecular structure is illustrated. However, the molecular stable structure search apparatus described above for the basic form is not limited to this embodiment. For example, a stable structure is searched for by changing a molecular structure by moving a plurality of atoms at once using molecular orbital calculation. The form to do may be sufficient.

  In the above description, as an example of the search unit in the basic mode described above, the search unit 450 that sets the tunneling term to “0” when the potential energy of the molecule becomes smaller than a predetermined threshold is exemplified. However, the search unit in the basic form described above is not limited to this. For example, the tunneling term may gradually approach “0” as the molecular potential energy decreases.

  Moreover, in the above, the energy calculation part 440 which uses two types of tunneling terms selectively was illustrated as an example of the energy calculation part in the type of application form which uses a some tunneling term properly. However, the energy calculation unit in the above-described type of application is not limited to this, and for example, three or more types of tunneling terms may be used properly.

100 Computer 110 Main Body 111 CPU
112 Main memory 113 HDD
114 CD-ROM drive 115 I / O interface 110A CD-ROM loading slot 120 Image display device 121 Monitor 130 Keyboard 140 Mouse 200 CD-ROM
300 Molecular Structure Search Program 310 Initial Structure Data Input Unit 320 Atom Transfer Unit 330 Movement Determination Unit 340 Energy Calculation Unit 350 Search Unit 360 Search Result Storage / Display Unit 400 Molecular Stable Structure Search Device 410 Initial Structure Data Input Unit 420 Atom Transfer Unit 430 Movement determination unit 440 Energy calculation unit 450 Search unit 460 Search result storage / display unit

Claims (6)

An atom moving unit that moves the coordinates of the atoms to be moved among the atoms that make up the molecule for a molecule in which each of a plurality of atoms is arranged at each coordinate point and the potential energy changes as the atom moves. When,
The current movement of the movement target atom in the atomic movement unit is a first type movement in which movement of the movement target atom is hindered by an energy barrier of potential energy or a second type excluding the first type movement. A movement determination unit for determining whether the movement,
Depending on whether the movement of the movement target atom is the first type movement or the second type movement, the energy barrier depends on the coordinate points of a plurality of atoms constituting the molecule, respectively. An energy calculator that calculates a potential energy of the molecule based on a first potential function that includes a tunneling term that reduces and a second potential function obtained by removing the tunneling term from the first potential function;
The movement of the atom to be moved by the atom moving unit and the calculation of the potential energy of the molecule by the energy calculating unit are performed according to the decrease of the calculated potential energy in the case of the first type of movement. A search unit for searching for coordinate points of a plurality of atoms constituting the molecule, wherein the potential energy of the molecule is minimized by alternately repeating while reducing the influence of the tunneling term of the function including the disappearance of the effect; A molecular stable structure search device comprising:   The movement determination unit determines that the movement of the movement target atom is the first type movement when the movement of the movement target atom is a movement accompanied by a change in a dihedral angle in the molecular structure of the molecule. The molecular stable structure search apparatus according to claim 1, wherein the apparatus is a molecular stable structure search apparatus.   The search unit is configured to extinguish an influence of a tunneling term of the first potential function when a potential energy smaller than a predetermined threshold is calculated as the potential energy of the molecule. Item 3. The molecular stable structure search device according to Item 1 or 2.   The energy calculation unit has a plurality of tunneling terms having different values associated with each atomic group when the molecule is divided into a plurality of atomic groups, and the movement of the movement target atom is the first 4. In the case of one type of movement, the potential energy of the molecule is calculated using a tunneling term corresponding to the atomic group to which the moving target atom belongs. The molecular stable structure search device according to claim 1. Executed in a computer, on the computer,
An atom moving unit that moves the coordinates of the atoms to be moved among the atoms that make up the molecule for a molecule in which each of a plurality of atoms is arranged at each coordinate point and the potential energy changes as the atom moves. When,
The current movement of the movement target atom in the atomic movement unit is a first type movement in which movement of the movement target atom is hindered by an energy barrier of potential energy or a second type excluding the first type movement. A movement determination unit for determining whether the movement,
Depending on whether the movement of the movement target atom is the first type movement or the second type movement, the energy barrier depends on the coordinate points of a plurality of atoms constituting the molecule, respectively. An energy calculator that calculates a potential energy of the molecule based on a first potential function that includes a tunneling term that reduces and a second potential function obtained by removing the tunneling term from the first potential function;
The movement of the atom to be moved by the atom moving unit and the calculation of the potential energy of the molecule by the energy calculating unit are performed according to the decrease of the calculated potential energy in the case of the first type of movement. A search unit for searching for coordinate points of a plurality of atoms constituting the molecule, wherein the potential energy of the molecule is minimized by alternately repeating while reducing the influence of the tunneling term of the function including the disappearance of the effect; A stable molecular structure search program characterized by constructing An atomic movement process in which the coordinates of the target atom among the atoms that make up the molecule are moved on the data of a molecule in which each of the atoms is arranged at each coordinate point and the potential energy changes as the atom moves. When,
The current movement of the movement target atom in the atomic movement process is a first type movement in which movement of the movement target atom is hindered by an energy barrier of potential energy, or a second type excluding the first type movement. A movement determination process for determining whether it is movement;
Depending on whether the movement of the movement target atom is the first type movement or the second type movement, the energy barrier depends on the coordinate points of a plurality of atoms constituting the molecule, respectively. An energy calculation process for calculating the potential energy of the molecule based on a first potential function that includes a tunneling term that reduces, and a second potential function obtained by removing the tunneling term from the first potential function;
The movement of the atom to be moved by the atomic movement process and the calculation of the potential energy of the molecule by the energy calculation process are performed according to the decrease of the calculated potential energy in the case of the first type of movement. A search process for searching for coordinate points of a plurality of atoms constituting the molecule, in which the potential energy of the molecule is minimized by alternately repeating while reducing the influence of the tunneling term of the function including the disappearance of the effect. A molecular stable structure search method comprising:

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