CN109147867A - A kind of group's Advances in protein structure prediction based on dynamic fragment length - Google Patents

Abstract

A kind of group's Advances in protein structure prediction based on dynamic fragment length, for each target conformation, half conformation individual is randomly choosed from current population and establishes sub- population, and population is ranked up according to energy value, and a conformation is randomly choosed in conformation in the top to instruct to make a variation；In mutation process, multiple fragment lengths are designed, and its probability selected is calculated according to the success rate in early period of each fragment length, select probability is then based on according to the mode of roulette, a fragment length is selected to carry out segment exchange, realize mutation process.The present invention provides a kind of precision of prediction and the higher group's Advances in protein structure prediction based on dynamic fragment length of search efficiency.

Description

A kind of group's Advances in protein structure prediction based on dynamic fragment length

Technical field

The present invention relates to a kind of biological information, intelligent optimization, computer application field more particularly to a kind of bases In group's Advances in protein structure prediction of dynamic fragment length.

Background technique

Nineteen sixty-five, Nirenberg and Khorana etc. have found triplet genetic code (i.e. the first genetic code), and DNA is with three A nucleotide is that one group of codon translates to protein amino acid sequence (i.e. prlmary structure of protein)；And protein is only rolled over Its specific biological function could be generated by building up specific three-dimensional structure (i.e. tertiary protein structure).Relative to the first heredity Password, the corresponding relationship (i.e. the second genetic code or code of folding) between protein sequence primary structure and its tertiary structure It is still unsolved mystery.In order to solve protein folding this " asking for century ", more and more there is grinding for different discipline backgrounds The person of studying carefully participates, and especially for terminal-protein structure prediction of protein folding procedure, it is extensive to receive scientific circles Concern and research.For opposing proteins fold, protein structure prediction has stronger practicability, only acquisition protein Three-dimensional structure, could really realize gene diagnosis, and be finally reached gene therapy purpose.

Currently, the experimental method of measurement protein three-dimensional structure includes X-ray crystal diffraction, multi-dimensional nmr (NMR) With electron cryo-microscopy etc..X-ray crystal diffraction is current measurement protein structure most efficient method, and precision achieved is other What method cannot compare, major defect is that protein crystal is difficult to cultivate and the period of crystal structure determination is longer；NMR method The conformation of protein in the solution can directly be measured, but it is big to the requirement of sample, purity requirement is high, can only measure at present Small protein.Secondly, these experimental determining methods are expensive, the three-dimensional structure for measuring a protein needs hundreds of thousands Dollar, however, the primary amino acid sequences of one protein of measurement only need 1000 dollars or so, so as to cause protein sequence and Wide gap between three-dimensional structure measurement is increasing.Therefore, such as how computer is tool, with algorithm appropriate, from amino Acid sequence, which sets out, directly predicts the three-dimensional structure of protein, becomes a kind of important research topic in current biological informatics.

Ab initio prediction method is current most effective Advances in protein structure prediction.According to thermodynamics hypothesis, minimum energy Conformation be considered as conformation closest to native state.Therefore, it in ab initio prediction method, is evaluated using energy function each The quality of conformation, and search for using optimization method the conformation of minimum energy.In order to reduce the complexity of optimization algorithm, and mention High precision of prediction, ab initio prediction method selects albumen similar with search sequence from existing protein pool, and is directed to each residue Corresponding fragment library is established in position.In search process, new structure is generated by selecting segment to carry out assembling from corresponding fragment library As, and made a variation by segment exchange of the tripe systems as between.However, in mutation process, the fragment length that is exchanged Determination is the work of a challenge, and too long will lead to of fragment length destroys more excellent conformation, and fragment length is too short and can reduce calculation Method search speed, to influence search speed and precision of prediction.

Therefore, there is defects in terms of precision of prediction and search efficiency for existing Advances in protein structure prediction, need It improves.

Summary of the invention

In order to overcome precision of prediction and the lower deficiency of search efficiency, the present invention of existing Advances in protein structure prediction to mention A kind of precision of prediction and the higher group's Advances in protein structure prediction based on dynamic fragment length of search efficiency out.

The technical solution adopted by the present invention to solve the technical problems is:

A kind of group's Advances in protein structure prediction based on dynamic fragment length, the described method comprises the following steps:

1) sequence information of testing protein is inputted, and from ROBETTA server (http://www.robetta.org/) On obtain fragment library；

2) parameter setting: setting population scale NP, crossover probability CR, temperature factor KT, maximum number of iterations G_max, segment Length collection l={ l₁,l₂,...,l_M, the select probability p of each fragment length_m, m=1,2 ..., M, and initialize the number of iterations G=0, wherein M is the scale of fragment length collection；

3) segment assembling is randomly choosed from the corresponding fragment library in each residue position generates initial configurations population P_initial={ C₁, C₂,...,C_NP, wherein C_i, i={ 1,2 ..., NP } is i-th of conformation individual in population P；

4) energy value of each conformation individual in current population is calculated according to Rosetta Score3；

5) to each conformation C in population_i, i ∈ 1,2 ..., and NP } it performs the following operations:

5.1) by conformation C_iRegard target conformation as, selects NP/2 conformation at random from current population and set up sub- population, so The sub- population is ranked up from low to high according to energy afterwards；

5.2) from the preceding NP/5 conformation of the sub- population after sequence, one and C is randomly choosed_iDifferent conformations, is denoted as C_lbest；

5.3) three different and and C are randomly choosed from current population_iAnd C_lbestDifferent conformation C_a、C_bAnd C_c；

5.4) roulette algorithm is utilized, according to the select probability of each fragment length, is concentrated from fragment length and chooses one Fragment length l_m；

5.5) respectively from C_a、C_bAnd C_cThe different length in one residue position of middle random selection is l_mSegment replace conformation C_lbestThe segment of middle corresponding position generates variation conformation C_mutant；

5.6) random to generate a decimal R between 0 and 1, if R < CR, from conformation C_iIn randomly select a length For l_mSegment replacement variation conformation C_mutantThe segment of middle corresponding position, and a random fragment assembling is carried out, to generate survey Try conformation C_trial；Otherwise variation conformation is directly subjected to a random fragment assembling and generates test conformation C_trial；

5.7) test conformation C is calculated according to Rosetta score3 energy function_trialEnergy value；

If 5.8) C_trialEnergy value be less than C_iEnergy value, then C_trialReplace C_i；Otherwise according to Boltzmann probabilityReceive C_trial, wherein Δ E is C_trialEnergy value and C_iEnergy value miss absolute value of the difference；

If 5.9) C_trialReceived in step 5.8), then number of success of m-th of fragment length in g generation

6) g=g+1 updates the select probability p of each fragment length according to formula (1) if g > 20_m, m=1, 2,...,M；

If 7) g > G_max, then the final pre- geodesic structure of conformation conduct of minimum energy is exported, otherwise return step 5).

Technical concept of the invention are as follows: be directed to each target conformation, half conformation individual is randomly choosed from current population Sub- population is established, and population is ranked up according to energy value, and randomly chooses a conformation in conformation in the top to refer to Lead variation；In mutation process, multiple fragment lengths are designed, and it is calculated according to the success rate in early period of each fragment length Then the probability selected is based on select probability according to the mode of roulette and a fragment length is selected to carry out segment exchange, real Existing mutation process.It is higher based on Advances in protein structure prediction that the present invention provides a kind of precision of prediction and search efficiency.

Beneficial effects of the present invention are shown: on the one hand, being instructed to make a variation by local optimum conformation, can not only be kept The diversity of conformation, and search speed can be accelerated；On the other hand, segment exchange is carried out according to dynamic fragment length, added Interactive process between fast difference albumen, improves search efficiency.

Detailed description of the invention

Fig. 1 is that group's Advances in protein structure prediction based on dynamic fragment length carries out structure prediction to protein 1GYZ When conformation update schematic diagram.

Fig. 2 is that group's Advances in protein structure prediction based on dynamic fragment length carries out structure prediction to protein 1GYZ When obtained conformation distribution map.

Fig. 3 is that group's Advances in protein structure prediction based on dynamic fragment length carries out structure prediction to protein 1GYZ Obtained tomograph.

Specific embodiment

The invention will be further described below in conjunction with the accompanying drawings.

Referring to Fig.1~Fig. 3, a kind of group's Advances in protein structure prediction based on dynamic fragment length, including following step It is rapid:

1) sequence information of testing protein is inputted, and from ROBETTA server (http://www.robetta.org/) On obtain fragment library；

2) parameter setting: setting population scale NP, crossover probability CR, temperature factor KT, maximum number of iterations G_max, segment Length collection l={ l₁,l₂,...,l_M, the select probability p of each fragment length_m, m=1,2 ..., M, and initialize the number of iterations G=0, wherein M is the scale of fragment length collection；

3) segment assembling is randomly choosed from the corresponding fragment library in each residue position generates initial configurations population P_initial={ C₁, C₂,...,C_NP, wherein C_i, i={ 1,2 ..., NP } is i-th of conformation individual in population P；

4) energy value of each conformation individual in current population is calculated according to Rosetta Score3；

5) to each conformation C in population_i, i ∈ 1,2 ..., and NP } it performs the following operations:

5.1) by conformation C_iRegard target conformation as, selects NP/2 conformation at random from current population and set up sub- population, so The sub- population is ranked up from low to high according to energy afterwards；

5.2) from the preceding NP/5 conformation of the sub- population after sequence, one and C is randomly choosed_iDifferent conformations, is denoted as C_lbest；

5.3) three different and and C are randomly choosed from current population_iAnd C_lbestDifferent conformation C_a、C_bAnd C_c；

5.4) roulette algorithm is utilized, according to the select probability of each fragment length, is concentrated from fragment length and chooses one Fragment length l_m；

5.5) respectively from C_a、C_bAnd C_cThe different length in one residue position of middle random selection is l_mSegment replace conformation C_lbestThe segment of middle corresponding position generates variation conformation C_mutant；

5.6) random to generate a decimal R between 0 and 1, if R < CR, from conformation C_iIn randomly select a length For l_mSegment replacement variation conformation C_mutantThe segment of middle corresponding position, and a random fragment assembling is carried out, to generate survey Try conformation C_trial；Otherwise variation conformation is directly subjected to a random fragment assembling and generates test conformation C_trial；

5.7) test conformation C is calculated according to Rosetta score3 energy function_trialEnergy value；

If 5.8) C_trialEnergy value be less than C_iEnergy value, then C_trialReplace C_i；Otherwise according to Boltzmann probabilityReceive C_trial, wherein Δ E is C_trialEnergy value and C_iEnergy value miss absolute value of the difference；

If 5.9) C_trialReceived in step 5.8), then number of success of m-th of fragment length in g generation

6) g=g+1 updates the select probability p of each fragment length according to formula (1) if g > 20_m, m=1, 2,...,M；

If 7) g > G_max, then the final pre- geodesic structure of conformation conduct of minimum energy is exported, otherwise return step 5).

The α unfolded protein 1GYZ that the present embodiment sequence length is 60 is embodiment, a kind of based on dynamic fragment length Group's Advances in protein structure prediction, wherein comprising the steps of:

1) sequence information of testing protein is inputted, and from ROBETTA server (http://www.robetta.org/) On obtain fragment library；

2) parameter setting: setting population scale NP=50, crossover probability CR=0.5, temperature factor KT=2, greatest iteration Number G_max=1000, fragment length collection l={ 3,6,9,12 }, i.e. l₁=3, l₂=6, l₃=9, l₄=12, each fragment length Select probability p_m=0.5, m=1,2 ..., M, and initialize the number of iterations g=0, wherein M=4；

3) segment assembling is randomly choosed from the corresponding fragment library in each residue position generates initial configurations population P_initial={ C₁, C₂,...,C_NP, wherein C_i, i={ 1,2 ..., NP } is i-th of conformation individual in population P；

4) energy value of each conformation individual in current population is calculated according to Rosetta Score3；

5) to each conformation C in population_i, i ∈ 1,2 ..., and NP } it performs the following operations:

5.1) by conformation C_iRegard target conformation as, selects NP/2 conformation at random from current population and set up sub- population, so The sub- population is ranked up from low to high according to energy afterwards；

5.2) from the preceding NP/5 conformation of the sub- population after sequence, one and C is randomly choosed_iDifferent conformations, is denoted as C_lbest；

5.3) three different and and C are randomly choosed from current population_iAnd C_lbestDifferent conformation C_a、C_bAnd C_c；

5.4) roulette algorithm is utilized, according to the select probability of each fragment length, is concentrated from fragment length and chooses one Fragment length l_m；

5.5) respectively from C_a、C_bAnd C_cThe different length in one residue position of middle random selection is l_mSegment replace conformation C_lbestThe segment of middle corresponding position generates variation conformation C_mutant；

5.6) random to generate a decimal R between 0 and 1, if R < CR, from conformation C_iIn randomly select a length For l_mSegment replacement variation conformation C_mutantThe segment of middle corresponding position, and a random fragment assembling is carried out, to generate survey Try conformation C_trial；Otherwise variation conformation is directly subjected to a random fragment assembling and generates test conformation C_trial；

5.7) test conformation C is calculated according to Rosetta score3 energy function_trialEnergy value；

If 5.8) C_trialEnergy value be less than C_iEnergy value, then C_trialReplace C_i；Otherwise according to Boltzmann probabilityReceive C_trial, wherein Δ E is C_trialEnergy value and C_iEnergy value miss absolute value of the difference；

If 5.9) C_trialReceived in step 5.8), then number of success of m-th of fragment length in g generation

6) g=g+1 updates the select probability p of each fragment length according to formula (1) if g > 20_m, m=1, 2,...,M；

If 7) g > G_max, then the final pre- geodesic structure of conformation conduct of minimum energy is exported, otherwise return step 5).

The α unfolded protein 1GYZ for being 60 using sequence length has obtained the protein with above method as embodiment Nearly native state conformation, lowest mean square root deviation areAverage root-mean-square deviation isPre- geodesic structure is as shown in Figure 3.

Described above is that the present invention is obtained as example using protein 1GYZ as a result, and non-limiting implementation model of the invention It encloses, various changes and improvements is done to it under the premise of without departing from range involved by basic content of the present invention, should not exclude at this Except the protection scope of invention.

Claims (1)

1. a kind of group's Advances in protein structure prediction based on dynamic fragment length, it is characterised in that: the method includes with Lower step:

1) sequence information of testing protein is inputted, and obtains fragment library from ROBETTA server；

2) parameter setting: setting population scale NP, crossover probability CR, temperature factor KT, maximum number of iterations G_max, fragment length Collect l={ l₁,l₂,...,l_M, the select probability p of each fragment length_m, m=1,2 ..., M, and initialize the number of iterations g= 0, wherein M is the scale of fragment length collection；

3) segment assembling is randomly choosed from the corresponding fragment library in each residue position generates initial configurations population P_initial={ C₁, C₂,...,C_NP, wherein C_i, i={ 1,2 ..., NP } is i-th of conformation individual in population P；

4) energy value of each conformation individual in current population is calculated according to Rosetta Score3；

5) to each conformation C in population_i, i ∈ 1,2 ..., and NP } it performs the following operations:

5.1) by conformation C_iRegard target conformation as, selects NP/2 conformation at random from current population and set up sub- population, then basis Energy is from low to high ranked up the sub- population；

5.2) from the preceding NP/5 conformation of the sub- population after sequence, one and C is randomly choosed_iDifferent conformations, is denoted as C_lbest；

5.3) three different and and C are randomly choosed from current population_iAnd C_lbestDifferent conformation C_a、C_bAnd C_c；

5.4) roulette algorithm is utilized, according to the select probability of each fragment length, is concentrated from fragment length and chooses a segment Length l_m；

5.5) respectively from C_a、C_bAnd C_cThe different length in one residue position of middle random selection is l_mSegment replace conformation C_lbestIn The segment of corresponding position generates variation conformation C_mutant；

5.6) random to generate a decimal R between 0 and 1, if R < CR, from conformation C_iIn randomly select a length be l_m Segment replacement variation conformation C_mutantThe segment of middle corresponding position, and a random fragment assembling is carried out, to generate test structure As C_trial；Otherwise variation conformation is directly subjected to a random fragment assembling and generates test conformation C_trial；

5.7) test conformation C is calculated according to Rosetta score3 energy function_trialEnergy value；

If 5.8) C_trialEnergy value be less than C_iEnergy value, then C_trialReplace C_i；Otherwise according to Boltzmann probabilityReceive C_trial, wherein Δ E is C_trialEnergy value and C_iEnergy value miss absolute value of the difference；

If 5.9) C_trialReceived in step 5.8), then number of success of m-th of fragment length in g generation

6) g=g+1 updates the select probability p of each fragment length according to formula (1) if g > 20_m, m=1,2 ..., M；

If 7) g > G_max, then the final pre- geodesic structure of conformation conduct of minimum energy is exported, otherwise return step 5).