140
2, June 2011
Protein 3D HP Model Folding Simulation Using a Hybrid of Genetic Algo-
rithm and Particle Swarm Optimization
Cheng-Jian Lin and Shih-Chieh Su
Abstract1
Given the amino-acid sequence of a protein, the
prediction of a proteins tertiary structure is known
as the protein folding problem. The protein folding
problem in the hydrophobic-hydrophilic lattice
model is the problem of finding the lowest energy
conformation. This is the NP-complete problem. In
order to enhance the procedure performance for
predicting protein structures, a hybrid genetic-based
particle swarm optimization (PSO) is proposed.
Simulation results indicate that our approach out-
performs the existing evolutionary algorithms. The
method can be applied successfully to the protein
folding problem based on the three-dimensional hy-
drophobic-hydrophilic lattice model.
Keywords: Protein structure prediction, three- dimen-
sional HP lattice model, particle swarm optimization,
genetic algorithm.
1. Introduction
The prediction of protein structure from its amino-acid
sequence is one of the most prominent problems in
computational biology. A proteins function depends
mainly on its tertiary structure, which in turn depends on
its primary structure. Folding mistakes will create pro-
teins with abnormal shapes which are the main causes of
numerous diseases, such as cystic fibrosis, Alzheimers,
and mad cow. If it were possible to predict proteins ter-
tiary structures of from their sequences with high accu-
racy, it would be able to treat these diseases better. The
knowledge of protein tertiary structures also has other
applications, such as in the structure-based drug design
field [1]. Currently, protein structures are primarily de-
termined by techniques such as MRI (magnetic reso-
nance imaging) and X-ray crystallography, which are
expensive in terms of equipment, computation, and time.
Corresponding Author: C.-J. Lin is with the Department of Computer
Science and Information Engineering, National Chin-Yi University of
Technology, No. 35, Lane 215, Sec. 1, Chung-Shan Rd., Taiping City,
Taichung County, Taiwan, 411
E-mail: cjlin@ncut.edu.tw
Manuscript received 11 Jan. 2010; revised 15 Sept. 2010; accepted 27
Dec. 2010.
2011 TFSA
International Journal of Fuzzy Systems, Vol. 13, No.
Additionally, these techniques require isolation, purifi-
cation, and crystallization of the target protein. Compu-
tational approaches to protein structure prediction are
therefore very attractive. The difficulties in solving pro-
tein structure prediction problems stems from two major
challenges: (1) finding good measures to verify the
qualities of candidate structures; and (2) given such
measures, determining optimal or close-to-optimal
structures for a given amino-acid sequence [2]. The Hy-
drophobic-Polar model (HP model) is a simplified model
which has become very popular. The HP model is one of
the widely used models.
For the 2D HP model, a two-dimensional square lat-
tice is widely used [1]-[12]. The real application of evo-
lutionary algorithms [2]-[4] to the two-dimensional HP
model was found to be impracticable. It has been
claimed that the characterization completely depends on
the accuracy of identifying a meaningful structure. The
biological activity of a protein depends on its
three-dimensional (tertiary) structure. Thus, to determine
that structure has become one of the most central prob-
lems in bioinformatics. The 3D HP model generally
adopts a three dimensional cubic lattice. It is observed
that the characterization completely depends on the ac-
curacy of identifying the data points which are mean-
ingful [13]. Fortunately, the three-dimensional HP model
is similar to the real protein structure.
Recently, many researchers [2],[14]-[18] have used
evolutionary algorithms, such as the genetic algorithms
(GA), for solving the protein folding problem. The Ge-
netic Algorithm (GA) is a method of optimizing random
searching by multiple pathways. In order to replace fixed
rules with random calculation in the searches for proper
conformation, the GA is chosen as the solution in the
PSP problem in our study. In general, the GA gives very
robust performance due to its inherent advantages; how-
ever, its efficiency in solving the PSP still needs further
improvements. There are two key operations in the GA,
i.e., crossover and mutation. Crossover is capable of
linking two different chromosomes very efficiently to
form a new conformation, while mutation will not be
restricted by local optimum. The limits of the HP model,
on the other hand, will generate many invalid conforma-
tions after operations of crossover and mutation, which
results in high reduction of the predication efficiency.
Therefore, some researchers have proposed various hy-
C.-J. Lin et al.: Protein 3D HP Model Folding Simulation Using a Hybrid of Genetic Algorithm and Particle Swarm Optimization 141

brid methods aiming to improve the efficiency of GA

recently. The key-point to improve GA lies primarily in
operating optimization of crossover and mutation, while
relative methods have been developed in this direction.
For example, the particle swarm optimization (PSO) has
been chosen to select better mutation in genes. Lin et al.
[19]-[20] has achieved good results in engineering and
computing science by applying the PSO to optimize the
mutation process.
In this paper, we focus on improving the
three-dimensional hydrophobic-polar (HP) lattice model
[18] and propose a hybrid genetic-based particle swarm
optimization (HGA-PSO) to tackle the PSP problem in
the 3D HP model. The simulation results indicate that
our proposed 3D HP model in protein folding problem Figure 1. An optimal conformation for the sequence
can yield much better performance than other current (HP)2PH(HP)2(PH)2HP(PH)2 in 3D lattice model.
evolutionary algorithms.
The remainder of this paper is structured as follows. B. Calculating The Free Energy
Section 2 sets out the preliminaries and the formal defi- One of the most popular lattice models, the HP model,
nition of the protein folding problem in the 3D HP lattice features just two bead types: H (hydrophobic or
model. Section 3 describes our approach in detail. The non-polar) and P (hydrophilic or polar). An instance is
hybrid genetic-based particle swarm optimization is pre- shown in Figure 1 for the 3D HP lattice model [6]. The
sented. Experimental results obtained by our method and black beads denote the hydrophobic amino acid and
by other methods are compared in Section 4. Finally, the white beads denote the hydrophilic. The dotted line de-
conclusion is given in Section 5. notes the H-H contacts (free energy) in the conformation,
which are assigned an energy value of -1. The free en-
2. Preliminaries ergy is minimum; the number of H-H contacts is the
maximum. Figure 1 shows a protein structure with 11
A. The 3D HP Protein Folding Problem H-H contacts (energy= -11). Since the native state of a
Lattice proteins are highly simplified computer mod- protein generally corresponds to the lowest free energy
els of proteins which are used to investigate protein state for the protein, the optimal conformation in the HP
folding. Dill [1] proposes the hydrophobic-polar model. model is the one that has the maximum number of H-H
Because proteins are such large molecules, containing contacts which gives the lowest energy value.
hundreds or thousands of atoms, it is not possible with The free energy for the protein can be calculated by
current technology to simulate more than a few micro- using the following formulae [21]:
seconds of their behavior in complete atomic detail.
Hence, folding of real proteins cannot be simulated in a
computer operation. Lattice proteins, however, are sim- (1)
plified in two ways: the amino acids are modeled as sin-
gle beads rather than by every atom, and the beads are
restricted to a rigid (usually cubic) lattice. This simplifi- (2)
cation means they can quickly fold to their energy min- where the parameter
ima in a time short enough to be simulated. Lattice pro-
teins are made to resemble real proteins by introducing
an energy function [9], a set of conditions which specify
the energy of interaction between neighboring beads, (3)
usually taken to be those occupying adjacent lattice sites. Hence, the protein folding problem can be trans-
The energy function mimics the interactions, which in- formed into an optimization problem, i.e., to calculate
clude hydrophobic and hydrogen bonding effects, be- the minimal free energy of the protein folding conforma-
tween amino acids in real proteins. The beads are di- tion. As a result, the following problem can be formally
vided into types, and the energy function specifies the defined: given an HP sequence s = s1, s2, ..., sn, find an
interactions, depending on the bead type, just as different energy-minimizing conformation of s; that is: find c*
types of amino acid interact differently.
C(s) such that E(c*) = min{E(c) | c C}, where C(s) is
142
the set of all valid conformations for s [22].
3. Methods
A. Particle Swarm Optimization
The idea of particle swarm optimization was origi-
nally introduced by Kennedy and Eberhart in 1995 to
study social and cognitive behavior [23]-[24]. The idea
originated in studies on the synchronous flocking of
birds and the schooling of fish. The PSO has come to be
widely used as a problem solving method in engineering
and computer science. This algorithm has several highly
desirable attributes, including a basic algorithm that is
very easy to understand and implement. It is similar in
some ways to evolutionary algorithms, but requires less
computational bookkeeping and generally fewer lines of
code.
In the PSO, the trajectory of each individual in the
search space is adjusted by dynamically altering the ve-
locity of each particle, according to its own flight ex-
perience and the flight experience of the other particles
in the search space. The position vector and the velocity
vector of the ith particle in the D-dimensional search
space can be represented by X i = ( xi1 , xi 2 , xi 3 ,......, xid )
and Vi = ( i1 , i 2 , i 3 ,......, id ) , respectively. According to a
user-defined fitness function, suppose that the best posi-
tion of each particle (which corresponds to the best fit-
ness value obtained by the particle at that time)
is Pi = ( pi1 , pi 2 , pi 3 ,......, pid ) and that the fittest particle
found so far is Pg = ( p g1 , p g 2 , p g 3 ,......, p gd ) . Then the
new velocities and the positions of the particles for the
next fitness evaluation are calculated using the following
two equations:
idk +1 = idk + c1 rand () ( Pid xidk ) + c 2 rand () ( Pgd xidk ) (2)
xidk +1 = xidk + vidk +1
where c1 and c2 are constants known as acceleration co-
efficients, and rand () are two separately generated uni-
formly distributed random numbers in the range [0,1].
The concept of the updated velocity is illustrated in
Figure 2. The first part of Equation (2) represents the
previous velocity, which provides the necessary mo-
mentum for particles to roam across the search space.
The second part of Equation (2), known as the cogni-
tive component, represents the personal thinking of
each particle. The cognitive component encourages the
particles to move toward their own best positions found
up to that point. The third part of Eq. (2) is known as the
social component, which represents the collaborative
effect of the particles in finding the global optimal solu-
tion. The social component always pulls the particles
toward the best global particle found so far. Changing
International Journal of Fuzzy Systems, Vol. 13, No. 2, June 2011
velocity enables every particle to search around its best
individual and global positions. After the new velocity is
obtained, the particle updates the position by following
Eq. (3). When every particle is updated, the fitness value
of each particle is calculated again. If the fitness value of
the new particle is higher than those of the local best,
then the local best will be replaced with the new particle;
and further, if the local best is better than the current
global best, then we replace the global best with the local
best in the swarm.
Figure 2. The diagram of the updated velocity in the PSO.
B. Particle Swarm Optimization
Figure 3 shows the flowchart of the proposed hybrid
genetic-based particle swarm optimization (HGA-PSO).
The hybrid learning algorithm works with a population
of candidate solutions. At each generation, the n best
individuals of the population are selected based on their
fitness (the minimum free energy). The details are as
follows:
z Initialization step: If the input amino acid sequence is
of length n, then each individual in the population is a
string of length n-1 over the symbols = {R, L, F, B, D,
U}, and that denotes a valid conformation in the 3D
square lattice [10]. The symbols R, L, F, B, D and U
are used to denote the fold directions right, left, for-
(3) ward, backward, up and down in the encoding scheme,
respectively. An initial population is generated ran-
domly and initializes an n-1 dimensional space within
a fixed range. Figure 4 shows that the adopted schemes
for representing internal movements are absolute di-
rections.
z Reproduction step: Reproduction is a process in
which individual strings are copied according to their
fitness value. In this study, we use the roulette-wheel
selection method [25]: a simulated roulette is spun for
this reproduction process. The best performing indi-
viduals (that is, the whole of the top half is considered
as best) [26] advance to the next generation. The other
half is generated to perform crossover and mutation
operations on individuals in the top half of the parent
generation.
C.-J. Lin et al.: Protein 3D HP Model Folding Simulation Using a Hybrid of Genetic Algorithm and Particle Swarm Optimization
Figure 3. Flowchart of the proposed hybrid learning algo-
rithm.
z Mutation step: When the mutation points are selected,
Figure 4. The schemes of the internal coordinates (the black
cube represents the current location).
z Crossover Step: Reproduction directs the search to-
ward the best existing individuals but does not create
any new individuals. In nature, an offspring has two
parents and inherits genes from both. The main opera-
tion used when working on the parents is the crossover
operation, the operation of which occurred for a se-
lected pair with a crossover rate that was set to 0.8 in
this study. The first step is to select the individuals
from the population for the crossover. Tournament se-
lection [25] is used to select the top-half of the best
performing individuals [26]. The individuals are
143
crossed and separated using a two-point crossover op-
eration. In Figure 5, new individuals are created by
exchanging the sites direction between points i and j
(the selected sites of an individuals parents). After
this operation, the individuals with poor performances
are replaced by the newly produced offspring.
Figure 5: Two-point crossover operation between the i and j
chromosomes.
Figure 6. Mutation operation using PSO with the ith-jth
chromosomes.
the mutation of an individual is as shown in Figure 6.
For the HP protein folding problem, every amino-acid
residue owns each folding direction that is unique to
the site. GA is incapable of efficient mutation opera-
tions aimed at each residue. Therefore, we propose a
mutation operation based on particle swarm optimiza-
tion. Equation (2) represents variations of the folding
direction to the next generation. We calculate the dif-
ference between the current particle and the local best
particle. We also calculate the difference between the
current particle and the global best particle. Equation
(3) represents variations of the current position that
updates the particles. Through the mutation step, only
one best child can survive to replace its parent and en-
ter the next generation. This involves PSO changing
the local structure between i and j, where i and j are
two randomly determined sequence positions, such
that 1 i j n (the length of protein sequence).
Hence, we employ the merits of PSO to improve the
mutation mechanism. In order to avoid entrapment in a
local optimal solution and to ensure the searching ca-
pability of the near global optimal solution, mutation
plays an important role in PSO. It is a recently in-
vented high performance optimizer that possesses sev-
144 International Journal of Fuzzy Systems, Vol. 13, No. 2, June 2011

eral highly desirable attributes, including the fact that the best direction in a local search by three methods.
the basic algorithm is very easy to understand and im- The new folding direction is superior to the original
plement. It requires less computational memory and direction. If the new folding direction is not better
fewer lines of code. Each particle has a velocity vector than the original direction, the original direction will
and a position vector x to represent a possible not change
solution. There are three possibilities for each particle
during evolution: (1) Remain itself; (2) move towards
the present optimum; each particle remembers its
own personal best position that it has found, called the
local best; and (3) move towards the best population it
has encountered. Each particle is also influenced by
the best position found by any particle in the swarm,
called the global best.
z Local search step: After mutation, a local search is

the same as the crossover operation. New individuals

are created by changing the sites direction between
point i and point j. Two motions have produced a new
direction. The new folding direction is superior to the
original direction. One of the two motions is selected
by competition. If the new folding direction is not bet-
ter than the original direction, the original direction
will not change. A local search can perform an inten-
sive search for a new and better solution. This is simi-
lar to the mutation operation. The local search is dif-
ferent from the mutation operation in terms of the rules.
A local search has system rules and effectively finds a
local solution. Figure 8. (a) The clockwise rotation motion; (b) the coun-
a) Opposite motion: As shown in Figure 7, the motion terclockwise rotation motion.
of a local structure is in the opposite direction. We
can change the local structure between two randomly z Update local best and global best step: In this step,
determined sequence positions. All the residue di- we update the local best and the global best. If the fit-
rections are right, down, backward, up, backward, ness value of a particle is higher than that of the local
right to left, up, forward, down, forward, left. The best, then the local best will be replaced with the parti-
inversion method can advance in the opposite direc- cle; and if the local best is better than the current
tion, which is the direction of repulsion. global best, than we replace the global best with the
local best in the swarm.

Table 1. The residue fold direction with local search.

The z-axis The y-axis The x-axis
Op-
Direction fixed fixed fixed
posite
CW CCW CW CCW CW CCW
Right (R) L B F D U R R
Figure 7. All the residues move in the opposite direction. Left (L) R F B U D L L
Forward (F) B R L F F U D
Backward (B) F L R B B D U
b) Rotation motion: The structure can rotate clockwise Up (U) D B F D U R R
(CW) or counterclockwise (CCW) relative to the lo- Down (D) U F B U D L L
cal structure, as shown in Figure 8. Figures 8 (a) and Right (R) L U U R L B F
Left (L) R D D L R F B
8 (b) represent clockwise rotation and counterclock-
wise rotation, respectively. The illustrations show
that left to right transformation from the top specifi- z Update local best and global best step: In this step,
cally involves the fixed x-axis, the fixed y-axis, and we update the local best and the global best. If the fit-
the fixed z-axis. Therefore, we can build Table 1, ness value of a particle is higher than that of the local
which lists the relationship between the original di- best, then the local best will be replaced with the parti-
rections and the transformed directions. We choose cle; and if the local best is better than the current
global best, than we replace the global best with the
C.-J. Lin et al.: Protein 3D HP Model Folding Simulation Using a Hybrid of Genetic Algorithm and Particle Swarm Optimization 145

local best in the swarm.
z Termination Condition: The algorithm is run for a
maximum of 50,000 iterations or until minimum free
energy is achieved in the sequence. The best member
of the population is then returned.
the genetic-based particle swarm optimization mutation
process, was able to obtain a new minimal energy value
for protein instances 6 and 7. In HGA-PSO, the standard
deviation was less than 1. Other algorithms are very sen-
sitive.

4. Simulation Results

In this section, our algorithm is compared with the

standard genetic algorithm, backtracking-EA [27], ag-
ing-AIS [28], and ClonalgI [29]. In Table 2, the 7 chosen
HP instances are standard benchmarks used to test the
searching ability of the algorithms. The free energy is
the optimal or best-known energy value. Hi ,Pi e()i in-
dicates i repetitions of the relative symbol or subse-
quence. Sequences 1 to 7 were introduced in [12]. These
sequences have been used as the benchmark for the HP
model.

Table 2. 3D lattice HP benchmarks.

Seq. Length Protein Sequence Energy
1 20 (HP)2PH(HP)2(PH)2HP(PH)2 -11
2 24 H2P2(HP2)6H2 -13
3 25 P2HP2(H2P4)3H2 -9
4 36 P(P2H2)2P5H5(H2P2)2P2H(HP2)2 -18
5 48 P2H(P2H2)2P5H10P6(H2P2)2HP2H5 -29
6 50 H2(PH)3PH4PH(P3H)2P4(HP3)2HPH4(PH)3PH2 -26
7 60 P(PH3)2H5P3H10PHP3H12P4H6PH2PHP -49

We give the structure obtained by our algorithm as

follows. Fifty independent runs of the algorithms were
performed. Sequences 1 to 4 and sequence 6 used a 100
population size. Sequences 5 and 7 used a 300 popula-
tion size. The crossover rate and mutation rate were set
to 0.8 and 0.3, respectively. For all sequences, 50,000
iterations of our algorithm were run. We also chose c1 =
c2 = 1 in Equation (2). These sets of parameters were
experimentally determined. The structure of 7 protein
sequences can be clearly seen in Fig. 9. Figure 9. Results of the structure of 7 protein sequences.
In Backtracking-EA [27], the experiments were done
with an elitist generational EA (population size = 100, Table 3. The simulation results obtained from the proposed
crossover rate = 0.9, mutation rate = 0.01) using linear algorithms compared with the methods given in the literature.
ranking selection (=2.0). A maximum number of 105 Backtrack-
Ag-
HGA ing-EA ClonalgI
evaluations were enforced. The Aging-AIS used the Seq. Length E*
-PSO
GA
[27]
ing-AIS
[29]
standard parameter values k = 10, dup = 2, and c = 0.4, [28]

as described in [28]. B cells had the aging parameter B 1 20 -11 -11 -11 -11 -11 -11
2 24 -13 -13 -13 -13 -13 -13
= 5, with the memory B cells Bm = 10, and a maximum 3 25 -9 -9 -9 -9 -9 -9
number of evaluations equal to 105. ClonalgI used the 4 36 -18 -18 -18 -18 -18 -18
10 individuals in the population. The duplication rate 5 48 -29 -29 -25 -25 -29 -29
was equal to 4, the mutation rate was equal to 0.6, and 6 50 -26 -26 -23 -23 -23 -26
7 60 -49 -49 -37 -39 -41 -48
the termination criterion was 105 evaluations.
The simulation results are summarized in Table 4 in
The simulation results are summarized in Table 4 in
terms of the best found free energy (best), mean, and
terms of the best found free energy (best), mean, and
standard deviation (SD). The HGA-PSO, which adopts
standard deviation (SD). The HGA-PSO, which adopts
146 International Journal of Fuzzy Systems, Vol. 13, No. 2, June 2011

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Cheng-Jian Lin received the B.S.
degree in electrical engineering from
Ta-Tung University, Taiwan, R.O.C., in
1986 and the M.S. and Ph.D. degrees in
electrical and control engineering from
the National Chiao-Tung University,
Taiwan, R.O.C., in 1991 and 1996.
Currently, he is a full Professor of Com-
puter Science and Information
Engineering Department, National Chin-Yi University of
Technology, Taichung County, Taiwan, R.O.C. His current
research interests are soft computing, pattern recognition, in-
telligent control, image processing, bioinformatics, and FPGA
design.
Shih-Chieh Su received his B.Sc.
Degree in Information Management from
Ling-Tung University of Technology,
Taiwan, R.O.C., in 2006 and his M.Sc.
Degree in Computer Science and
Information Engineering from Chaoyang
University of Technology, Taiwan,
R.O.C., in 2006. Currently, he is
studying for a PhD in Computer Science
and Information in the Engineering Department, National
Chung Cheng University, Chiayi County, Taiwan, R.O.C. His
current research interests are evolutionary computation, meta-
heuristic algorithms, and bioinformatics.