CN105808973B - One kind is based on interim shifty group's conformational space method of sampling - Google Patents

One kind is based on interim shifty group's conformational space method of sampling Download PDF

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CN105808973B
CN105808973B CN201610121504.8A CN201610121504A CN105808973B CN 105808973 B CN105808973 B CN 105808973B CN 201610121504 A CN201610121504 A CN 201610121504A CN 105808973 B CN105808973 B CN 105808973B
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omega
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张贵军
周晓根
俞旭锋
郝小虎
王柳静
徐东伟
李章维
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Zhejiang University of Technology ZJUT
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Abstract

One kind is comprised the following steps based on interim shifty group's conformational space method of sampling：Under differential evolution algorithm frame, entire algorithmic procedure is divided into multiple stages, one group policy pond is set to each stage, when algorithm reaches some stage, from its corresponding tactful pond, a strategy is randomly selected, based on segment package technique, new test conformation individual is generated, so as to improve conformation ability in sampling and convergence speed of the algorithm；Simultaneously distance spectrum constraint is introduced in conformation selection link, when the energy for testing conformation is higher than target conformation, then compare the range difference of the two, if the range difference for testing individual is smaller, then with certain probability acceptance test conformation, so as to which bootstrap algorithm samples to obtain, energy is lower and the conformation of more reasonable structure, improves the precision of prediction of algorithm.

Description

One kind is based on interim shifty group's conformational space method of sampling
Technical field
The present invention relates to bioinformatics, computer application field more particularly to one kind based on interim mostly tactful Group's conformational space method of sampling.
Background technology
Many of biological cell protein (long-chain formed by more than 2 kinds of amino acid), these macromoleculars are in organism In play an important role, for complete biological function it is most important.Protein molecule reacted on a molecular scale its structure with Important relationship between function, different protein play a different role in organism.The space structure of protein is often Determine its function, therefore, the prediction of protein structure the design, drug design, protein stability of new albumen are predicted with And the interaction modeling between protein is most important.
The structure of protein is generally divided into four levels：Primary structure (amino acid sequence), secondary structure are (between skeletal atom The partial structurtes that are formed of interaction), tertiary structure (space structure that secondary structure accumulation in a wide range of is formed) and four Level structure (describes the interaction between different subunits).Especially, the three-dimensional structure (native state structure) of protein is to understand The key of the biological function of protein.Protein three-dimensional structure can pass through the experimental methods such as nuclear magnetic resonance and X-ray crystal diffraction It obtains, however these experimental determining methods are not only time-consuming but also extremely expensive, for some protein for being not easy to crystallize not It is applicable in.Therefore, according to Anfinsen the thermodynamics hypothesis conformation of minimum energy (have be considered as native state structure), very More computational algorithms are proposed for protein structure prediction.
Protein tertiary structure is carried out by computing technique and is usually directed to an energy function for evaluating very expensive, energy Function surface usually has thousands of degree of freedom and substantial amounts of locally optimal solution.In so huge higher-dimension conformational space Sample extremely difficult.In order to carry out conformational space search, ab initio prediction method is usually first according to Knowledge based engineering coarse grain The Global optimal solution that energy model obtains conformational space is spent, refine then is carried out to its corresponding conformation, so as to obtain prediction knot Structure.Therefore, ab initio prediction method needs solve two problems：1. suitable energy function is established to weigh in protein molecule not Interaction between homoatomic；2. effective conformational space searching method is proposed to search for energy Global optimal solution.
Differential evolution algorithm (DE) has proved to be Stochastic Global Optimization Algorithms most simple and powerful in evolution algorithm. Since it has the advantages of simple structure and easy realization, the advantages that strong robustness and fast convergence rate, has been successfully applied to protein tertiary structure. However, with the growth of amino acid sequence, protein molecule system degree of freedom also increases, and is sampled and obtained using traditional group's algorithm The Global optimal solution of large-scale protein texture image space becomes the work of a challenge；Traditional Swarm Evolution algorithm is to conformation During spatial sampling, the region where can navigating to minimal solution quickly in early period, but the later stage since local enhancement ability is weaker, Convergence rate is slower, and is easily ensnared into local optimum, can not obtain Global optimal solution.
Therefore, existing group's conformational space using method in terms of ability in sampling and convergence rate Shortcomings, it is necessary to It improves.
The content of the invention
In order to overcome the shortcomings of existing group's conformational space method of sampling in terms of ability in sampling and convergence rate, this hair It is bright provide it is a kind of promoted ability in sampling, improve convergence rate, improve precision of prediction based on interim shifty group's conformation Spatial sampling procedures.
The technical solution adopted by the present invention to solve the technical problems is：
One kind is comprised the following steps based on interim shifty group's conformational space method of sampling, the method for sampling：
1) list entries information is given；
2) according to sequence information from QUARK servers (http://zhanglab.ccmb.med.umich.edu/ QUARK/ distance spectrum file profile, rp are obtained on)iFor the residue pair recorded in distance spectrum, DiBetween the residue pair Distance, wherein i ∈ (1, N), N are residue in distance spectrum to quantity；
3) arrange parameter：Population Size NP, the iterations G of algorithm, intersect factor CR, and stage factor s puts iterative algebra G=0；
4) initialization of population：NP initial configurations C is generated by list entriesi, i={ 1 ..., NP }, to each conformation individual Whole position segment assemblings；
5) for each conformation individual C in populationi, i ∈ { 1,2,3 ..., NP } make Ctarget=Ci, CtargetRepresent mesh Conformation individual is marked, following operation is performed and obtains variation conformation Cmutant：
5.1) generation positive integer rand1, rand2, rand3 ∈ { 1,2,3 ... NP }, and rand1 ≠ rand2 at random ≠rand3≠i；Regenerate 4 random integers randrange1, randrange2, randrange3, randrange4；Wherein Randrange1 ≠ randrange2, randrange3 ≠ randrange4 ∈ { 1,2 ..., L }, L are sequence length；
5.2) a=min (randrange1, randrange2), b=max (randrange1, randrange2), k ∈ are made [a,b]；Make c=min (randrange3, randrange4), d=max (randrange3, randrange4), p ∈ [c, d]； Wherein min expressions take the minimum value of two numbers, and max represents to take the maximum of two numbers
If 5.3) g ＜ sG, following operation is performed：
5.3.1) if randn (1,3)=1, then use Crand2Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega, then by gained Crand1Segment is carried out to assemble to obtain variation conformation Cmutant, the random integer generated between [1,3] of wherein randn (1,3) expressions；
5.3.2) if randn (1,3)=2, then use Crand2Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand3 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.3.3) if randn (1,3)=3, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.4) sG≤g ＜ 2sG, following operation is performed：
5.4.1 ascending order arrangement) is carried out to the conformation in entire population according to energy, then from preceding 0.5NP conformation individual In select a conformation at random and be denoted as Cpbest；
5.4.2) if randn (1,3)=1, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.4.3) if randn (1,3)=2, then use CpbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.4.4) if randn (1,3)=3, then use CpbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.5) g >=2sG, following operation is performed：
5.5.1 entire population stochastic averagina) is divided into three groups, judges current goal conformation CtargetThe group at place, Ran Houcong The conformation C of minimum energy is selected in corresponding grouplbest；
5.5.2) if randn (1,3)=1, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.5.3) if randn (1,3)=2, then use ClbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.5.4) if randn (1,3)=3, then use ClbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
6) to the conformation C that makes a variationmutantPerform crossover operation：
6.1) random number rand4, rand5, wherein rand4 ∈ (0,1), rand5 ∈ (1, L) are generated；
6.2) basisPerform crossover process：If random number Rand4≤CR, variation conformation CmutantSegment rand5 replace with target conformation CtargetIn corresponding segment, it is otherwise direct etc. In variation conformation Cmutant；
7) to target conformation CtargetWith test conformation CtrailMake choice operation；
7.1) C is calculatedtargetAnd CtrailEnergy：E(Ctarget) and E (Ctrail)；
If 7.2) E (Ctarget)>E(Ctrail), then CtrailReplace Ctarget, and step 8) is gone to, otherwise continue to execute step 7.3)；
7.3) target conformation C is calculated respectivelytargetWith test conformation CtrailMiddle residue is to rpiThe distance between and distance spectrum In the distance between corresponding distance differenceWith
7.4) judgeWithValue whether be more than 6, if more than 6, then it is made to be equal to 6, removes some range differences It is worth larger abnormal numerical value；
7.5) respectively calculate target conformation and test conformation in all residues to the distance between with distance in distance spectrum it The average value of difference,
If 7.6) ▽ Dtrail＞ ▽ Dtarget, then step 8) is gone to；
If 7.7) ▽ Dtrail＜ ▽ Dtarget, then the random number rand6 between one (0,1) is generated, if rand6 is less than 0.2, then use CtrailReplace Ctarget, otherwise enter step 8)；
8) i=i+1；Judge whether i is more than or equal to NP, if it is 9) g=g+1, otherwise enters step；
9) operating procedure 5 of iteration)~7), until meeting end condition.
The present invention technical concept be：Under differential evolution algorithm frame, entire algorithmic procedure is divided into multiple stages, it is right Each stage sets a group policy pond, when algorithm reaches some stage, from its corresponding tactful pond, randomly selects a plan Slightly, based on segment package technique, new test conformation individual is generated, so as to improve the convergence of conformation ability in sampling and algorithm speed Degree；Both distance spectrum constraint is introduced in conformation selection link simultaneously, when the energy for testing conformation is higher than target conformation, then compare Range difference, if the range difference of test individual is smaller, with certain probability acceptance test conformation, so as to which bootstrap algorithm samples Lower and more reasonable structure the conformation to energy improves the precision of prediction of algorithm.
The present invention, based on segment package technique, is set different under basic differential evolution algorithm frame in algorithm each stage New conformation generation strategy pond, a new conformation of generation is then randomly selected from tactful pond, to improve convergence speed of the algorithm And reliability, while distance restraint is added in selection link, the bootstrap algorithm region low and rational in infrastructure in energy is sampled, The ability in sampling of algorithm is improved on the whole, so as to improve precision of prediction.
Beneficial effects of the present invention are：Based on segment package technique, generated in each stage of algorithm using different conformations Strategy improves convergence speed of the algorithm and conformation ability in sampling；Distance spectrum introduces selection link, bootstrap algorithm as auxiliary constraint Sampling obtains the conformation of high quality.
Description of the drawings
Fig. 1 is structure when being sampled based on interim shifty group's conformational space method of sampling to protein 1AIL As updating schematic diagram.
The conformation that Fig. 2 is obtained when being based on interim shifty group's conformational space method of sampling protein 1AIL samplings Distribution map；
Specific embodiment
The invention will be further described below in conjunction with the accompanying drawings.
With reference to Fig. 1~2, one kind is comprised the following steps based on interim shifty group's conformational space method of sampling：
1) list entries information is given；
2) according to sequence information from QUARK servers (http://zhanglab.ccmb.med.umich.edu/ QUARK/ distance spectrum file profile, rp are obtained on)iFor the residue pair recorded in distance spectrum, DiBetween the residue pair Distance, wherein i ∈ (1, N), N are residue in distance spectrum to quantity；
3) arrange parameter：Population Size NP, the iterations G of algorithm, intersect factor CR, and stage factor s puts iterative algebra G=0；
4) initialization of population：NP initial configurations C is generated by list entriesi, i={ 1 ..., NP }, to each conformation individual Whole position segment assemblings；
5) for each conformation individual C in populationi, i ∈ { 1,2,3 ..., NP } make Ctarget=Ci, CtargetRepresent mesh Conformation individual is marked, following operation is performed and obtains variation conformation Cmutant：
5.1) generation positive integer rand1, rand2, rand3 ∈ { 1,2,3 ... NP }, and rand1 ≠ rand2 at random ≠rand3≠i；Regenerate 4 random integers randrange1, randrange2, randrange3, randrange4；Wherein Randrange1 ≠ randrange2, randrange3 ≠ randrange4 ∈ { 1,2 ..., L }, L are sequence length；
5.2) a=min (randrange1, randrange2), b=max (randrange1, randrange2), k ∈ are made [a,b]；Make c=min (randrange3, randrange4), d=max (randrange3, randrange4), p ∈ [c, d]； Wherein min expressions take the minimum value of two numbers, and max represents to take the maximum of two numbers
If 5.3) g ＜ sG, following operation is performed：
5.3.1) if randn (1,3)=1, then use Crand2Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega, then by gained Crand1Segment is carried out to assemble to obtain variation conformation Cmutant, the random integer generated between [1,3] of wherein randn (1,3) expressions；
5.3.2) if randn (1,3)=2, then use Crand2Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand3 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.3.3) if randn (1,3)=3, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.4) sG≤g ＜ 2sG, following operation is performed：
5.4.1 ascending order arrangement) is carried out to the conformation in entire population according to energy, then from preceding 0.5NP conformation individual In select a conformation at random and be denoted as Cpbest；
5.4.2) if randn (1,3)=1, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.4.3) if randn (1,3)=2, then use CpbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.4.4) if randn (1,3)=3, then use CpbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.5) g >=2sG, following operation is performed：
5.5.1 entire population stochastic averagina) is divided into three groups, judges current goal conformation CtargetThe group at place, Ran Houcong The conformation C of minimum energy is selected in corresponding grouplbest；
5.5.2) if randn (1,3)=1, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.5.3) if randn (1,3)=2, then use ClbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.5.4) if randn (1,3)=3, then use ClbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
6) to the conformation C that makes a variationmutantPerform crossover operation：
6.1) random number rand4, rand5, wherein rand4 ∈ (0,1), rand5 ∈ (1, L) are generated；
6.2) basisPerform crossover process：If random number Rand4≤CR, variation conformation CmutantSegment rand5 replace with target conformation CtargetIn corresponding segment, it is otherwise direct etc. In variation conformation Cmutant；
7) to target conformation CtargetWith test conformation CtrailMake choice operation；
7.1) C is calculatedtargetAnd CtrailEnergy：E(Ctarget) and E (Ctrail)；
If 7.2) E (Ctarget)>E(Ctrail), then CtrailReplace Ctarget, and step 8) is gone to, otherwise continue to execute step 7.3)；
7.3) target conformation C is calculated respectivelytargetWith test conformation CtrailMiddle residue is to the distance between rpi and distance spectrum In the distance between corresponding distance differenceWith
7.4) judgeWithValue whether be more than 6, if more than 6, then it is made to be equal to 6, removes some range differences It is worth larger abnormal numerical value；
7.5) respectively calculate target conformation and test conformation in all residues to the distance between with distance in distance spectrum it The average value of difference,
If 7.6) ▽ Dtrail＞ ▽ Dtarget, then step 8) is gone to；
If 7.7) ▽ Dtrail＜ ▽ Dtarget, then the random number rand6 between one (0,1) is generated, if rand6 is less than 0.2, then use CtrailReplace Ctarget, otherwise enter step 8)；
8) i=i+1；Judge whether i is more than or equal to NP, if it is 9) g=g+1, otherwise enters step；
9) operating procedure 5 of iteration)~7), until meeting end condition.
The protein 1AIL that the present embodiment is 73 using sequence length is embodiment, and one kind is based on interim shifty group The conformational space method of sampling, wherein comprising the steps of：
1) sequence information of protein 1AIL is given；
2) according to sequence information from QUARK servers (http://zhanglab.ccmb.med.umich.edu/ QUARK/ distance spectrum file profile, rp are obtained on)iFor the residue pair recorded in distance spectrum, DiBetween the residue pair Distance, wherein i ∈ (1, N), N=75 are residue in distance spectrum to quantity；
3) arrange parameter：Population Size NP=30, the iterations G=10000 of algorithm intersect factor CR=0.5, stage Factor s=1/3 puts iterative algebra g=0；
4) initialization of population：NP initial configurations C is generated by list entriesi, i={ 1 ..., NP }, to each conformation individual Whole position segment assemblings；
5) for each conformation individual C in populationi, i ∈ { 1,2,3 ..., NP } make Ctarget=Ci, CtargetRepresent mesh Conformation individual is marked, following operation is performed and obtains variation conformation Cmutant：
5.1) generation positive integer rand1, rand2, rand3 ∈ { 1,2,3 ... NP }, and rand1 ≠ rand2 at random ≠rand3≠i；Regenerate 4 random integers randrange1, randrange2, randrange3, randrange4；Wherein Randrange1 ≠ randrange2, randrange3 ≠ randrange4 ∈ { 1,2 ..., L }, L are sequence length；
5.2) a=min (randrange1, randrange2), b=max (randrange1, randrange2), k ∈ are made [a,b]；Make c=min (randrange3, randrange4), d=max (randrange3, randrange4), p ∈ [c, d]； Wherein min expressions take the minimum value of two numbers, and max represents to take the maximum of two numbers
If 5.3) g ＜ sG, following operation is performed：
5.3.1) if randn (1,3)=1, then use Crand2Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega, then by gained Crand1Segment is carried out to assemble to obtain variation conformation Cmutant, the random integer generated between [1,3] of wherein randn (1,3) expressions；
5.3.2) if randn (1,3)=2, then use Crand2Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand3 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.3.3) if randn (1,3)=3, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.4) sG≤g ＜ 2sG, following operation is performed：
5.4.1 ascending order arrangement) is carried out to the conformation in entire population according to energy, then from preceding 0.5NP conformation individual In select a conformation at random and be denoted as Cpbest；
5.4.2) if randn (1,3)=1, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.4.3) if randn (1,3)=2, then use CpbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.4.4) if randn (1,3)=3, then use CpbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.5) g >=2sG, following operation is performed：
5.5.1 entire population stochastic averagina) is divided into three groups, judges current goal conformation CtargetThe group at place, Ran Houcong The conformation C of minimum energy is selected in corresponding grouplbest；
5.5.2) if randn (1,3)=1, then use Crand1Corresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.5.3) if randn (1,3)=2, then use ClbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Amino acid institute p corresponding dihedral angle phi, psi, omega of segments of the upper position c to position d replace Crand1Upper same position institute Corresponding dihedral angle phi, psi, omega, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.5.4) if randn (1,3)=3, then use ClbestCorresponding to the amino acid k of segments of the upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to the amino acid p of segments of the upper position c to position d replace CtargetUpper same position institute Corresponding dihedral angle phi, psi, omega, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
6) to the conformation C that makes a variationmutantPerform crossover operation：
6.1) random number rand4, rand5, wherein rand4 ∈ (0,1), rand5 ∈ (1, L) are generated；
6.2) basisPerform crossover process：If random number Rand4≤CR, variation conformation CmutantSegment rand5 replace with target conformation CtargetIn corresponding segment, it is otherwise direct etc. In variation conformation Cmutant；
7) to target conformation CtargetWith test conformation CtrailMake choice operation；
7.1) C is calculatedtargetAnd CtrailEnergy：E(Ctarget) and E (Ctrail)；
If 7.2) E (Ctarget)>E(Ctrail), then CtrailReplace Ctarget, and step 8) is gone to, otherwise continue to execute step 7.3)；
7.3) target conformation C is calculated respectivelytargetWith test conformation CtrailMiddle residue is to the distance between rpi and distance spectrum In the distance between corresponding distance differenceWith
7.4) judgeWithValue whether be more than 6, if more than 6, then it is made to be equal to 6, removes some range differences It is worth larger abnormal numerical value；
7.5) respectively calculate target conformation and test conformation in all residues to the distance between with distance in distance spectrum it The average value of difference,
If 7.6) ▽ Dtrail＞ ▽ Dtarget, then step 8) is gone to；
If 7.7) ▽ Dtrail＜ ▽ Dtarget, then the random number rand6 between one (0,1) is generated, if rand6 is less than 0.2, then use CtrailReplace Ctarget, otherwise enter step 8)；
8) i=i+1；Judge whether i is more than or equal to NP, if it is 9) g=g+1, otherwise enters step；
9) operating procedure 5 of iteration)~7), until iterations G=10000 times.
The protein 1AIL for being 73 using sequence length has obtained the near natural of the protein as embodiment, with above method State conformation, it is 3.75 to run the average root-mean-square deviation between 30 obtained structures and native state structure, lowest mean square root Deviation is 2.83, and conformation update figure in conformation assemblage is as shown in Figure 1, the obtained conformation distribution map of sampling is as shown in Figure 2.
Described above is the excellent results that one embodiment that the present invention provides shows, it is clear that the present invention not only fits Above-described embodiment is closed, it can on the premise of without departing from essence spirit of the present invention and without departing from content involved by substantive content of the present invention Many variations are done to it to be carried out.

Claims (1)

1. one kind is based on interim shifty group's conformational space method of sampling, it is characterised in that：The conformational space sampling Method comprises the following steps：
1) list entries information is given；
2) distance spectrum file profile, rp are obtained from QUARK servers according to sequence informationjIt is residual for what is recorded in distance spectrum Base pair, DjFor the residue to the distance between, wherein j ∈ (1, N), N be distance spectrum in residue to quantity；
3) arrange parameter：Population Size NP, the iterations G of algorithm, intersect factor CR, and stage factor s puts iterative algebra g= 0；
4) initialization of population：NP initial configurations C is generated by list entriesi, i={ 1 ..., NP }, to each conformation individual all Position segment assembling；
5) for each conformation individual C in populationi, i ∈ { 1,2,3 ..., NP } make Ctarget=Ci, CtargetRepresent target structure As individual, perform following operation and obtain variation conformation Cmutant：
5.1) generation positive integer rand1, rand2, rand3 ∈ { 1,2,3 ... NP } at random, and rand1 ≠ rand2 ≠ rand3≠i；Regenerate 4 random integers randrange1, randrange2, randrange3, randrange4；Wherein Randrange1 ≠ randrange2, randrange3 ≠ randrange4 ∈ { 1,2 ..., L }, L are sequence length；
5.2) a=min (randrange1, randrange2) is made, b=max (randrange1, randrange2), k ∈ [a, b]；Make c=min (randrange3, randrange4), d=max (randrange3, randrange4), p ∈ [c, d]；Its Middle min expressions take the minimum value of two numbers, and max represents to take the maximum of two numbers
If 5.3) g ＜ sG, following operation is performed：
5.3.1) if randn (1,3)=1, then use Crand2Corresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega, then by gained Crand1Segment is carried out to assemble to obtain variation conformation Cmutant, the random integer generated between [1,3] of wherein randn (1,3) expressions；
5.3.2) if randn (1,3)=2, then use Crand2Corresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand3 Dihedral angle phi, psi, omega corresponding to p-th of amino acid of the segment of upper position c to position d replace Crand1Upper identical bits Corresponding dihedral angle phi, psi, omega are put, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.3.3) if randn (1,3)=3, then use Crand1Corresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to p-th of amino acid of the segment of upper position c to position d replace CtargetUpper identical bits Corresponding dihedral angle phi, psi, omega are put, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.4) sG≤g ＜ 2sG, following operation is performed：
5.4.1) according to energy in entire population conformation carry out ascending order arrangement, then from preceding 0.5NP conformation individual with Machine selects a conformation and is denoted as Cpbest；
5.4.2) if randn (1,3)=1, then use Crand1Corresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.4.3) if randn (1,3)=2, then use CpbestCorresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to p-th of amino acid of the segment of upper position c to position d replace Crand1Upper identical bits Corresponding dihedral angle phi, psi, omega are put, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.4.4) if randn (1,3)=3, then use CpbestCorresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to p-th of amino acid of the segment of upper position c to position d replace CtargetUpper identical bits Corresponding dihedral angle phi, psi, omega are put, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
If 5.5) g >=2sG, following operation is performed：
5.5.1 entire population stochastic averagina) is divided into three groups, judges current goal conformation CtargetThe group at place, then from correspondence Group in select the conformation C of minimum energylbest；
5.5.2) if randn (1,3)=1, then use Crand1Corresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace CpbestSame position corresponding to dihedral angle phi, psi, omega, then by gained CpbestSegment is carried out to assemble to obtain variation conformation Cmutant；
5.5.3) if randn (1,3)=2, then use ClbestCorresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace Crand1Same position corresponding to dihedral angle phi, psi, omega；Reuse Crand2 Dihedral angle phi, psi, omega corresponding to p-th of amino acid of the segment of upper position c to position d replace Crand1Upper identical bits Corresponding dihedral angle phi, psi, omega are put, then by gained Crand1Progress segment, which assembles to obtain, tests individual Cmutant；
5.5.4) if randn (1,3)=3, then use ClbestCorresponding to k-th of amino acid of the segment of upper position a to position b Dihedral angle phi, psi, omega replace CtargetSame position corresponding to dihedral angle phi, psi, omega；Reuse Crand1 Dihedral angle phi, psi, omega corresponding to p-th of amino acid of the segment of upper position c to position d replace CtargetUpper identical bits Corresponding dihedral angle phi, psi, omega are put, then by gained CtargetProgress segment, which assembles to obtain, tests individual Cmutant；
6) to the conformation C that makes a variationmutantPerform crossover operation：
6.1) random number rand4, rand5, wherein rand4 ∈ (0,1), rand5 ∈ (1, L) are generated；
6.2) basisPerform crossover process：If random number rand4 ≤ CR, variation conformation CmutantSegment rand5 replace with target conformation CtargetIn corresponding segment, be otherwise directly equal to make a variation Conformation Cmutant；
7) to target conformation CtargetWith test conformation CtrailMake choice operation；
7.1) C is calculatedtargetAnd CtrailEnergy：E(Ctarget) and E (Ctrail)；
If 7.2) E (Ctarget)>E(Ctrail), then CtrailReplace Ctarget, and step 8) is gone to, otherwise continue to execute step 7.3)；
7.3) target conformation C is calculated respectivelytargetWith test conformation CtrailMiddle residue is to rpjThe distance between with it is right in distance spectrum The distance between distance answered differenceWith
7.4) judgeWithValue whether be more than 6, if more than 6, then it is made to be equal to 6, remove some distance differences compared with Big abnormal numerical value；
7.5) calculate respectively all residues in target conformation and test conformation to the distance between and distance spectrum in distance difference Average value,
If 7.6) ▽ Dtrail＞ ▽ Dtarget, then step 8) is gone to；
If 7.7) ▽ Dtrail＜ ▽ Dtarget, then the random number rand6 between one (0,1) is generated, if rand6 is less than 0.2, Use CtrailReplace Ctarget, otherwise enter step 8)；
8) i=i+1；Judge whether i is more than or equal to NP, if it is 9) g=g+1, otherwise enters step；
9) operating procedure 5 of iteration)~7), until meeting end condition.
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