AU2021102886A4 - Method for Optimizing Protein Target Structure and a System Thereof - Google Patents
Method for Optimizing Protein Target Structure and a System Thereof Download PDFInfo
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Abstract
The present disclosure discloses a method for optimizing a protein target structure
and a system thereof. The method comprises the steps of: extracting a target structure
from a protein target database, wherein the target structure comprises a main chain
structure and a plurality of side chain structures, and the main chain structure is fixed;
rotating a plurality of dihedral angles of a plurality of side chain structures with three
degrees of freedom in sequence according to a set sequence, and judging whether the
number of the rotated side chain structures reaches the preset number of structures; if
not, continuing to rotate with three degrees of freedom; if so, optimizing and
intercepting the rotated side chain structure by a DFTB method; after interception,
rotating the remaining dihedral angles with three degrees of freedom, and optimizing
and intercepting the rotated side chain structure by a DFTB method after rotating every
dihedral angle once, until all dihedral angles of all side chain structures have been
searched. According to the present disclosure, an accurate and reliable target structure is
provided through a reliable conformation search method and structural optimization of
quantum chemical calculation.
101
Extracting a target structure from a protein target database, wherein the target structure
comprises a main chain structure and a plurality of side chain structures, and the main
chain structure is fixed.
102
Rotating a plurality of dihedral angles of a plurality of side chain structures with three
degrees of freedom in sequence according to a set sequence, and judging whether the
number of the rotated side chain structures reaches the preset number of structures
103
No
The number of the rotated side chain
structures reaches the preset
number of structures
104
Optimizing and intercepting the rotated side chain structure by a DFTB method
After interception, rotating the remaining dihedral angles with three degrees of 105
freedom, and optimizing and intercepting the rotated side chain structure by a DFTB
method after rotating every dihedral angle once, until all dihedral angles of all side
chain structures have been searched.
FIG. 1
10
Description
[01] The present disclosure relates to the technical field of protein target structure, in particular to a method for optimizing protein target structure and a system thereof.
[02] Modem drug research and development must rely on relevant computing software, and its functions are as follows: 1, generating all possible molecular structures by a computer; 2, modifying the generated molecules; 3, screening all the molecules through calculation and simulation, and selecting a small number of molecules whose calculation indexes meet the requirements from many candidates, so as to enter the next stage of synthesis experiment. There are millions of molecules involved in the above three aspects, so they must be realized by software on the computing platform. This calculation must be screened by calculating the interaction between drug molecules and related protein targets.
[03] However, the side chain structure information of the target structure extracted from a protein database by the existing method is imperfect. This is because the structure in protein database is generally obtained by an experimental method, and the measurement accuracy of the experimental method can well reflect the main chain structure. However, the acquisition of side chain structure requires higher experimental accuracy (less than 1.5A), which is difficult to achieve in most cases. Therefore, the side chain structure can only be obtained with the help of calculation methods, but the commonly used methods such as molecular force fields have poor accuracy and universality, so that the reliability of the given side chain structure is low.
[04] Using the protein target with an unreliable side chain structure to calculate the interaction between drugs and targets is an important factor causing the deviation of calculation results. The lack of screening caused by this deviation is a significant cause for the high cost of drug research and development.
[05] The existing method extracts target structures from protein databases, and the structures in protein databases are mainly obtained by experimental methods. The measurement of a main chain structure and a side chain structure requires different experimental resolution. The main chain is 4.5-6 Angstroms, while the resolution for distinguishing the shape and the direction of the side chain is less than 2.5 Angstroms. Therefore, the main chain structure obtained by experiments is relatively reliable, and the side chain structure is usually obtained with the help of a calculation method.
[061 The shortcomings of the commonly used calculation methods are reflected in two aspects, namely, the energy calculation accuracy is not high, and the sampling method is unreliable.
[07] The purpose of the present disclosure is to provide a method for optimizing a protein target structure and a system thereof, which provides an accurate and reliable target structure through a reliable conformation search method and structural optimization of quantum chemical calculation.
[08] To achieve the above purpose, the present disclosure provides the following scheme:
[09] A method for optimizing a protein target structure, comprising:
[10] extracting a target structure from a protein target database, wherein the target structure comprises a main chain structure and a plurality of side chain structures, and the main chain structure is fixed;
[11] rotating a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence; preset
[121 judging whether the number of the rotated side chain structures reaches the number of structures;
[131 if not, continuing to rotate with three degrees of freedom;
[14] if so, optimizing and intercepting the rotated side chain structure by a DFTB method;
[15] after interception, rotating the remaining dihedral angles with three degrees of freedom, and optimizing and intercepting the rotated side chain structure by a DFTB method after rotating every dihedral angle once, until all dihedral angles of all side chain structures have been searched.
[16] Further, the structure whose energy is ranked among top N is intercepted.
[171 Further, the structure with the energy range within 8kcal is intercepted.
[181 Further, the number of the preset structures is 6561.
[19] Further, the rotation period is 120 .
[20] Further, prior to rotating a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence, the method further comprises:
[21] numbering the side chain and the dihedral angle of the side chain.
[221 The present disclosure further provides a system for optimizing a protein target structure, comprising:
[23] a target structure extraction module, which is configured to extract a target structure from a protein target database, wherein the target structure comprises a main chain structure and a plurality of side chain structures, and the main chain structure is fixed;
[24] a first rotation module, which is configured to rotate a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence;
[25] a judging module, which is configured to judge whether the number of the rotated side chain structures reaches the preset number of structures;
[26] an optimizing and intercepting module, which is configured to optimize and intercept the rotated side chain structure by a DFTB method;
[27] a second rotation and optimizing and intercepting module, which is configured to rotate the remaining dihedral angles with three degrees of freedom, and optimize and intercept the rotated side chain structure by a DFTB method after rotating every dihedral angle once, until all dihedral angles of all side chain structures have been searched.
[28] According to the specific embodiment provided by the present disclosure, the present disclosure discloses the following technical effects.
[29] The method for optimizing a protein target structure provided by the present disclosure comprises the steps of: extracting a target structure from a protein target database, wherein the target structure comprises a main chain structure and a plurality of side chain structures, and the main chain structure is fixed; rotating a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence, and judging whether the number of the rotated side chain structures reaches the preset number of structures; if not, continuing to rotate with three degrees of freedom; if so, optimizing and intercepting the rotated side chain structure by a DFTB method; after interception, rotating the remaining dihedral angles with three degrees of freedom, and optimizing and intercepting the rotated side chain structure by a DFTB method after rotating every dihedral angle once, until all dihedral angles of all side chain structures have been searched. According to the present disclosure, an accurate and reliable target structure is provided through a reliable conformation search method and structural optimization of quantum chemical calculation, which is more in line with the real situation in the calculation of the interaction between drug molecules and the target, reducing the research and development cost and speed up research and development by improving the production efficiency in the initial stage.
[301 In order to explain the embodiments of the present disclosure or the technical scheme in the prior art more clearly, the drawings needed in the embodiments will be briefly introduced hereinafter. Obviously, the drawings in the following description are only some embodiments of the present disclosure. For those skilled in the art, other drawings can be obtained according to these drawings without paying creative labor.
[31] FIG 1 is a flow chart of a method for optimizing a protein target structure according to an embodiment of the present disclosure;
[32] FIG 2 is a schematic diagram for numbering dihedral angles of side chains according to an embodiment of the present disclosure;
[33] FIG. 3 is a schematic diagram of structure optimization and structure search (structure sampling).
[34] The technical scheme in the embodiments of the present disclosure will be described clearly and completely hereinafter with reference to the drawings in the embodiments of the present disclosure. Obviously, the described embodiments are only some embodiments of the present disclosure, rather than all of the embodiments. Based on the embodiments of the present disclosure, all other embodiments obtained by those skilled in the art without paying creative labor belong to the scope of protection of the present disclosure.
[35] The purpose of the present disclosure is to provide a method for optimizing a protein target structure and a system thereof, which provides an accurate and reliable target structure through a reliable conformation search method and structural optimization of quantum chemical calculation.
[36] In order to make the above objects, features and advantages of the present disclosure more obvious and understandable, the present disclosure will be further explained in detail hereinafter with reference to the drawings and specific embodiments.
[37] As shown in FIG. 1, the method for optimizing a protein target structure disclosed by the present disclosure comprises the following steps:
[38] Step 101: extracting a target structure from a protein target database, wherein the target structure comprises a main chain structure and a plurality of side chain structures, and the main chain structure is fixed;
[39] Step 102: rotating a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence, the rotation period is 120;
[401 Step 103: judging whether the number of the rotated side chain structures reaches the preset number of structures; if not, proceed to step 102, and if so, proceed to step 104;
[41] Step 104: optimizing and intercepting the rotated side chain structure by a DFTB method, intercepting the structure whose energy is ranked among top N, or intercepting the structure with the energy range within 8kcal.
[42] Step 105: after interception, rotating the remaining dihedral angles with three degrees of freedom, and optimizing and intercepting the rotated side chain structure by a DFTB method after rotating every dihedral angle once, until all dihedral angles of all side chain structures have been searched.
[431 Prior to rotating a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence, the method further comprises: numbering the side chain and the dihedral angle of the side chain.
[441 The above method will be described in detail below.
[451 1. The target structure is extracted from the existing protein target database. (the target structure is extracted from the target database, that is, the three-dimensional coordinates of each atom in the target)
[46] 2. The main chain structure is fixed. The main chain structure in the target database is reliable and the accuracy of the side chain structure is insufficient. Therefore, the purpose of this step is to fix the three-dimensional coordinates of the main chain atoms, and the following sampling and optimization are only for the side chains. The fixed atom adopts constraint parameters in the input file, and the implementation method is to use the Constraintst{} command in the input file of DFTB and fill in the serial number corresponding to the fixed atom in parentheses.
[47] 3. The side chains and dihedral angles of the side chains are numbered, where the numbers are numbers in FIG. 2, and each dihedral angle is named. As shown in FIG. 2, the first dihedral angle X(1,1) of the first side chain is rotated with three degrees of freedom. Then y( 2 ,1), x (3,1) are rotated in sequence ... Since the target region usually contains more than ten amino acid side chains, 6561 structures will be obtained after rotating to X(8 ,1). These structures are optimized by the DFTB method. The structure with the energy range within 8kcal or the energy ranked among top N is intercepted. One of the two conditions can be satisfied. The value of N is determined by the user, and it is recommended to choose 1000, which can not only ensure the diversity of structures, but also control the amount of calculation within a reasonable range.
[48] 4. Thereafter, one dihedral angle is selected to rotate with three degrees of freedom each time (here, the selection is completed by the program, and each dihedral angle is operated one by one according to the order specified in the previous step). This rotation means structure sampling, in which the concepts and relationships of sampling, 9 optimization and structure search are described in detail in FIG. 3. For example, x( ,1) is selected to rotate with three degrees of freedom, the number of structures is expanded by three times, and the obtained 3*N structures are optimized by the DFTB. The interception standard is the same as that in step 3. In this way, the x(1,n) search of all target side chains is completed.
[491 5. The second dihedral angle x (1,2) to X(n,2) of each side chain is searched in the above way. (According to the relevant chemical theory, the structure is a C-C bond
structure, and the rotation period is about 1200 . On the basis of the initial angle X of
the dihedral angle, 120 ° and 240 0 are added, respectively, namely the angles of x,
x+120 and x+240, which is "structure sampling". The "search" of the structure is the final result of "structure sampling" and "structure optimization", which is detailed in FIG. 3.) The number of structures is expanded by three times after each rotation with three degrees of freedom. The DFTB method is used to optimize the structure, and the low-energy stable structures with energy within 8kcal or ranked among top N are selected.
[50] 6. According to the above steps, all dihedral angles of all side chains are searched (the rotational degree of freedom of each dihedral angle is sampled in sequence, that is, the original angle value x is added with 120 degrees and 240 degrees respectively, and the meaning of search and optimization is illustrated in FIG. 3), and a series of low-energy conformations are obtained. e- i/kT
[51] ei
[52] where Pi is the probability of quantum state i, si is the energy of quantum state i, k is Boltzmann constant, T is the system temperature, and M is the number of quantum states the system has. Pi indicates the probability that the structure with energy ranking i exists at temperature T in the output result of step 5. The environment where the drug molecules play a role is human body temperature, and T is set at 37°C, s is the energy of the i-th structure in the output result of step 5; k is Boltzmann constant (physical constant k = 1.380649x 10-23J/k); the denominator part of the expression acts as a normalization parameter; the meaning of the whole formula is to show that the existence probability of each structure decreases exponentially with the increase of its energy at any temperature, and the probability that the real molecular structure falls into the structure set with the energy ranking within 8kcal/mol exceeds 99.9% at the human ambient temperature (37C). Because of the higher energy, the existence possibility of structures other than the result of step 5 is ignorable.
[53] In FIG. 3, the black curve represents the potential energy surface, and the real structure of the molecule is at the local minimum point of the potential energy surface. The goal of the present disclosure is to find out all the local minimum values within a certain energy range (the upper energy limit is generally selected between 3-8kcal as required); the upper black dot represents the value of a dihedral angle in the initial structure; the dotted arrow represents the structural optimization process, which is completed by a DFTB program in order to find the local minimum of energy near the initial structure. However, the structural optimization cannot obtain the local minimum of other regions, so that sampling operation is needed. The solid arrow represents the sampling operation. According to the relevant chemical theory, the dihedral angle
usually contains three local minima in the range of 0-360° . Therefore, the dihedral
angle in the initial structure is added with 1200 and 240 ° respectively in order to
make the sampling point fall into other areas containing local minima. The above operation of finding out local minima through sampling and optimization is referred to as "structure search".
[54] Drug research and development (chemical drugs and biological drugs) must be screened by calculating the interaction between drug molecules and related protein targets. However, the missing side chain information of the target structure extracted from protein database by the existing method is an important factor causing the deviation of calculation results. According to the target structure obtained by the present disclosure, an accurate and reliable target structure is provided through a reliable conformation search method and structural optimization of quantum chemical calculation, which is more in line with the real situation in the calculation of the interaction between drug molecules and the target, reducing the research and development cost and speed up research and development by improving the production efficiency in the initial stage.
[55] The present disclosure further provides a system for optimizing a protein target structure, comprising:
[56] a target structure extraction module, which is configured to extract a target structure from a protein target database, wherein the target structure comprises a main chain structure and a plurality of side chain structures, and the main chain structure is fixed;
[57] a first rotation module, which is configured to rotate a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence;
[58] a judging module, which is configured to judge whether the number of the rotated side chain structures reaches the preset number of structures;
[59] an optimizing and intercepting module, which is configured to optimize and intercept the rotated side chain structure by a DFTB method;
[601 a second rotation and optimizing and intercepting module, which is configured to rotate the remaining dihedral angles with three degrees of freedom, and optimize and intercept the rotated side chain structure by a DFTB method after rotating every dihedral angle once, until all dihedral angles of all side chain structures have been searched.
[611 In this specification, each embodiment is described in a progressive manner, and each embodiment focuses on the differences from other embodiments. It is sufficient to refer to the same and similar parts among each embodiment. Because the system disclosed in the embodiment corresponds to the method disclosed in the embodiment, it is described relatively simply, and the relevant points can be found in the description of the method.
[62] In the present disclosure, a specific example is applied to illustrate the principle and implementation of the present disclosure, and the explanation of the above embodiments is only used to help understand the method and its core idea of the present disclosure. At the same time, according to the idea of the present disclosure, there will be some changes in the specific implementation and application scope for those skilled in the art. To sum up, the contents of this specification should not be construed as limiting the present disclosure.
Claims (7)
1. A method for optimizing a protein target structure, comprising: extracting a target structure from a protein target database, wherein the target structure comprises a main chain structure and a plurality of side chain structures, and the main chain structure is fixed; rotating a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence; judging whether the number of the rotated side chain structures reaches the preset number of structures; if not, continuing to rotate with three degrees of freedom; if so, optimizing and intercepting the rotated side chain structure by a DFTB method; after interception, rotating the remaining dihedral angles with three degrees of freedom, and optimizing and intercepting the rotated side chain structure by a DFTB method after rotating every dihedral angle once, until all dihedral angles of all side chain structures have been searched.
2. The method for optimizing a protein target structure according to claim 1, wherein the structure whose energy is ranked among top N is intercepted.
3. The method for optimizing a protein target structure according to claim 1, wherein the structure with the energy range within 8kcal is intercepted.
4. The method for optimizing a protein target structure according to claim 1, wherein the number of the preset structures is 6561.
5. The method for optimizing a protein target structure according to claim 1,
wherein the rotation period is 120 ° .
6. The method for optimizing a protein target structure according to claim 1, wherein prior to rotating a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence, the method further comprises: numbering the side chain and the dihedral angle of the side chain.
7. A system for optimizing a protein target structure, comprising: a target structure extraction module, which is configured to extract a target structure from a protein target database, wherein the target structure comprises a main chain structure and a plurality of side chain structures, and the main chain structure is fixed; a first rotation module, which is configured to rotate a plurality of dihedral angles of a plurality of side chain structures with three degrees of freedom in sequence according to a set sequence; a judging module, which is configured to judge whether the number of the rotated side chain structures reaches the preset number of structures; an optimizing and intercepting module, which is configured to optimize and intercept the rotated side chain structure by a DFTB method; a second rotation and optimizing and intercepting module, which is configured to rotate the remaining dihedral angles with three degrees of freedom, and optimize and intercept the rotated side chain structure by a DFTB method after rotating every dihedral angle once, until all dihedral angles of all side chain structures have been searched.
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| US20170329892A1 (en) * | 2016-05-10 | 2017-11-16 | Accutar Biotechnology Inc. | Computational method for classifying and predicting protein side chain conformations |
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