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1
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Modeling
the third loop of short-chain snake venom neurotoxins: Roles of
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the
short-range and long-range interactions, Zhijie Liu, Weizhong
Li, Hongyu
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Zhang,
Yuzhen Han, Luhua Lai* [Full Manuscript---Text,
Fig 1, 2,
3, 4]
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[Abstract]
The influence of long-range interactions
on local structures is an important issue in understanding protein
folding process and protein structure stability. Using short-chain
snake venom neurotoxin as a model system, we have studied the conformational
properties of eight different loop III sequences either in the environment
of one of the short-chain neurotoxin-erabutoxin b (PDB ID 1nxb),
or in free state by Monte Carlo simulated annealing method. The
surrounding protein structure was found to be crucial in stabilizing
the loop conformation. Although all the eight peptides prefer type
V b turn in solution, three of them (KPGI, KPGV, KSGI) turn to type
II b turn and the other five (KKGI, KKGV, KNGI, KQGI, and KRGV)
are confined to more rigid type V b turn conformation in the protein
structure. Using flexible tetra-glycine-peptide to screen the backbone
conformational space in the protein environment also validates the
results. This study shows that long-range interactions do contribute
to the stability and the types of conformation for a surface loop
in protein, while short-range interactions may only provide candidate
conformations, which then have to be filtered by the long-range
interactions further.
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[Key
Words] long-range interactions, loop
modeling, protein structure stability, Monte Carlo simulated annealing,
snake venom neurotoxin, short-range interactions
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2
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Conformational
changes accompanying with the binding of protein and
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ligand,
Zhijie Liu, Lin Jiang, Weizhong Li, Yuzhen Han and Luhua Lai*
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[Abstract]
The binding of protein with its ligand can be generalized into two
major modes: direct binding with surface loops or binding associated
with hinge movement. Two different strategies were developed to
study the conformational variation in the binding process. For directive
loop binding, a combinatorial conformational library for the backbone
structure of the loop was built up, which includes all possible
sub-stable conformations of the loop during the binding procedure.
The library of conformations was subject to screening by rigid docking.
The Streptavidin complex was used as an example to explore the possibility
to build the combinatorial conformational library of loop backbone.
For hinge binding movement, step-by-step docking method has been
proposed and applied to HIV-1 protease and inhibitor system. The
results show that both methods can simulate the conformational variation
of proteins in the binding process successfully. The proposed methods
for studying the binding process of protein and ligand will be helpful
for protein and drug design.
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[Keywords]
protein ligand binding, docking, loop, hinge
binding movement, induced fit
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3
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Analysis
of designed protein sequences based on special folding motifs
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using
side-chain upbuilding method,
Zhijie
Liu, Weizhong Li, Yuzhen Han,
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Luhua
Lai*
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[Abstract
]Protein side-chain upbuilding method
has been widely applied in protein modeling, protein sequence mutation,
protein design and study of the interactions between protein receptor
and its ligand. Based on our developed "disturbing genetic algorithm
for protein side-chain upbuilding", each 100 new sequences were
designed for four kinds of folding motifs a, b, a/b and a+b respectively,
which constitutions were same to the represent crystal sequence
while homologies were distributed between 0 and 100%. Analysis of
the relationships between calculated energies to homologies of sequence
and calculated energies to percents of conservative residues showed
that, the energies could be decreased dramatically through improving
the homologies of designed sequences and the percents of the conservative
residues in general. While additional computations of a/b motif
also illustrated that there also were sequences of lower energies
distributed both in lower and higher homologous area, which might
imply that there was a trend that low homologous sequences could
form the similar folding motif during protein evolution. Contrast
to these new designed sequences, most of the sequences from known
crystal structures had relatively lower energies. It was found that
the calculated energy with our method was suitable to judge the
rationality of the sequence fitting to special structural folding
motif. The sequences which calculated energies were lower than the
energy cutoff, which is 3 percent higher than the energy of the
represent crystal native sequence, may be potentially well situated
sequence to the corresponding folding motif. Therefore, through
retaining the key residues and mutating rest residues, we may design
new stable proteins which have relatively lower energy than known
sequences and are more suitable to special folding motifs.
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[Keywords]
Protein side-chain upbuilding method, disturbing genetic algorithm
for upbuilding protein side-chains, folding motif, homology of sequence,
conservative residues, protein design
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4
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Beyond
rotamer library: Genetic Algorithm combined with Disturbing
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Mutation
process for upbuilding protein side-chains,
Zhijie
Liu, Weizhong Li,
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Shide
Liang, Yuzhen Han, Luhua Lai*
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[Abstract]
Rotamer libraries have been widely used in predicting side-chain
packing in protein structure. No matter how large the library is,
in many cases, the conformations of side-chains will deviate from
idealized values. In this work, disturbing genetic algorithm (DGA)
that incorporates the disturbing mutation process into the genetic
algorithm (GA) flow has been used for upbuilding protein side-chains.
The program also includes growing generation amount (GGA) method
that inherits the characteristics of the natural evolution process.
By repacking side-chains within proteins and at the protein-protein
interfaces using pseudo energy function of root mean standard deviation
(RMSD), the DGA method was found to combine the advantages from
both data-based GA method and ab initio modeling method. It is more
accurate than data-based method and is less computational demanding
than ab initio method. The DGA method also overcomes the incompleteness
and inaccuracy of rotamer library. Real energy function and parameters
have been developed for side-chain repacking in proteins and protein-protein
interfaces. The program with real energy functions have been used
in 31 examples of both protein and protein-protein complex systems
and gave reasonable results, the averaged veracities of the torsion
angles of c1 is 80.37% for the buried residues. This method will
find wide applications in protein modeling, protein design, and
protein-protein interaction studies.
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[Keywords]
rotamer
library, disturbing genetic algorithm (DGA), growing generation
amount (GGA) method, protein side-chain, protein-protein interface
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5
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Calculation
of protein surface loops using Monte-Carlo simulated annealing
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simulation,
Zhijie Liu, Fenglou Mao, Weizhong Li, Yuzhen Han and Luhua
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[Abstract]
A modified program for protein loop modelling is presented with
significant improvements on our pervious study (Zhang et al. 1997,
Biopolymers, Vol. 41, pp. 61-72), which is capable of sampling the
entire conformational space and identifying the low-energy candidates
by Monte-Carlo simulated annealing simulation and cluster analysis
method. Twenty flexible surface loops connecting different secondary
structures are selected to test the efficiency of this program.
The averaged deviations of backbone heavy atoms for four to eight-residue-loops
are 0.19, 0.27, 0.46, 0.41 and 0.87Å respectively. High speed
of calculation is reached with the simplified energy function and
grid-mapping method. As a comparison of single simulation, it takes
only four seconds for the simplest four-residue loop and forty-three
seconds for the most complex eight-residue loop on PII-350-Linux
platform.
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[Keywords]
Protein loop, Loop conformation, Loop structure, Loop modelling,
Monte-Carlo simulated annealing, cluster analysis, simplified energy
function, grid-mapping method
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6-7
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Construction
of protein binding site in scaffold structures, Shide Liang, Zhijie
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Liu,
Weizhong Li, and Luhua Lai*
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[Abstract]
We have developed a strategy for grafting protein-protein interface
based on the known crystal structure of ligand and receptor proteins
in complex. The functional residues at the ligand protein binding
interface are grafted onto a scaffold protein so that the mutated
scaffold protein will bind the receptor protein in the same manner
as the ligand protein. First, our method identifies key residues
and atoms involved in strong interaction with the receptor protein.
Secondly, this method searches the scaffold protein for combination
of candidate residues, among which the distance between any two
candidate residues is similar to that between relevant key interaction
residues in ligand protein. These candidate residues are mutated
to the ligand protein's key interaction residues correspondingly.
The scaffold protein is then superposed onto the ligand protein
based upon the coordinates of corresponding atoms which are assumed
to strongly interact with the receptor protein. Complementarity
between scaffold and receptor proteins is then evaluated. Scaffold
proteins with a low superposing rms difference and high complementary
score are accepted for further analysis. Then, the relative position
of the scaffold protein is adjusted so that the interfaces between
the scaffold and receptor proteins have a reasonable packing density.
Other mutations are also considered to reduce the desolvation energy
or bad steric contacts. Finally, the scaffold protein is cominimized
with the receptor protein and evaluated. To test the method, the
binding interface of barstar, the inhibitor of barnase, was grafted
onto small proteins with a residue number in the range of 86-95
in PDB. Four scaffold proteins with high complementary score are
accepted.
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[Keywords]
protein-protein interaction, grafting, barnase-barstar, protein
design
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8
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Protein
loops on structurally similar scaffolds: Database and conformational
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analysis,
Weizhong Li, Zhijie Liu and Luhua Lai* [Full
Manuscript--Text,
Fig]
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[Abstract]
A general problem in comparative modelling and protein design is
the conformational evaluation of loops with certain sequence in
specific environmental protein frameworks. Loops of different sequences
and structures on similar scaffolds are common in the Protein Data
Bank (PDB). In order to explore both structural and sequential diversity
of them, a database of loops connecting similar secondary structure
fragments is constructed by searching the database of families of
structurally similar proteins (FSSP) and PDB. A total of 84 loop
families having 2 to 13 residues are found among the well determined
structures of resolution better than 2.5 Å. 8 a-a, 20 a-b,
19 b-a and 37 b-b families are identified. Every family contains
more than 5 loop motifs. In each family, no loops share same sequence
and all the frameworks are well superimposed. 43 new loop classes
are distinguished in the database. The structural variability of
loops in homologous proteins are examined and shown in 44 families.
Motif families are characterized with geometric parameters and sequence
patterns. The conformations of loops in each family are clustered
into subfamilies using average linkage cluster analysis method.
Information such as geometric properties, sequence profile, sequential
and structural variability in loop, structural alignment parameters,
sequence similarities, clustering results are provided. Correlations
between the conformation of loops and loop sequence, motif sequence
and global sequence of PDB chain are examined in order to find how
loop structures depend on their sequences and how they are affected
by the local and global environment. Strong correlations (R > 0.75)
are only found in 24 families. The best R-value is 0.98. The database
is available through the Internet.
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[Keywords]
protein loop, database, loop structure, loop conformation, loop
modelling
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9-10
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Combination
of disturbing mutation method with genetic algorithm in
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upbuilding
side chains of proteins, Zhijie Liu, Weizhong Li, Yuzhen Han,
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Luhua
Lai*
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[Abstract]
Based on the rotamer library, we proposed a method called Disturbing
Genetic Algorithm (DGA), which combined disturbing mutation with
Genetic Algorithm (GA). The method has characters of general GA
and searching modeling methods. Using the RMSD function and real
energy function, we upbuilt side chains of proteins and the interface
residues of protein complexes. The result shows that DGA is obviously
superior to GA and can reproduce the side chain conformations of
proteins successfully.
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[Keywords]
rotamer library, Genetic Algorithm, Disturbing Genetic Algorithm,
Searching Modeling Method
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11-12
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Rational
screenning in combinatorial peptide libraries of protein functional
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loop,
Weizhong Li, Zhijie Liu, Shide Liang, Yuzhen Han, Luhua Lai*
[Full
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[Abstract]
Redesigning the sequences of protein loops is a frequent practice
in protein design. Based on the new results of protein loop database
analysis, a rational computer simulation strategy is proposed to
obtain functional proteins, which exploits a fast and accurate program
to calculate the protein loop conformation, and at the same time,
combines molecular docking method with combinatorial chemistry strategy
to screen the combinatorial peptide library of protein loops. The
characteristics of this method is that it separates the conformation
computation of backbone from that of side chain and incorporates
side chain growth into the docking procedure , therefore greatly
reduces the computation by converting the huge computation on explosive
conformations to relatively smaller computation on limited canonical
backbone structures and side chain growth. This method can be practically
used in screening combinatorial peptide libraries of protein loops.
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[Keywords]
protein loop, protein design, molecular docking, combinatorial peptide
library
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13
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Calculation
of conformation for loops in snake venom neurotoxin, Liu Zhijie,
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Zhang
Hongyu, Han Yuzhen, Lai Luhua*
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[Abstract]
The loop region on protein surface is important for ligand-receptor
docking. However, its conformation is difficult to calculate because
of its flexibility. We have developed a procedure of Monte Carlo
Simulation Annealing Method for calculation of loops. It is based
on the simplified Potential (soft-Sphere Potential) and the Terminal
Restricted Potential. We have calculated loops in snake venom neurotoxin
and found all the conformation of the eight loops is b-turn. Polyglycine
is used to search the backbone conformation.
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[Keywords]
the loop region, Monte Carlo Simulation Annealing method, the simplified
potential, the soft-sphere potential, the terminal restricted potential,
snake venom neurotoxin, b-turns.
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14
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Roles
of the short-range and long-range interactions on protein loop
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conformations,
Yuzhen Han, Zhijie Liu, Weizhong Li, Luhua Lai
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[Abstract]
Short peptides in proteins can be classified in to two groups according
to whether they will always take a conserved conformation: conserved
peptides are those that will always take the same conformation independent
of protein environment; variable peptides are those that will change
conformation under different protein environment. Structurally conserved
peptides may act as nucleation site in protein folding. Roos. Et.al
studied the conformational properties of the blocked tetrapeptides
for the third loop by experimental methods and by potential energy
calculations. Their results indicate short range interactions are
important in determining the conformation of the first group. But
additional long range interactions are necessary in defining the
b-bend conformation of the latter group in protein. Zhang. Et.al.
developed an efficient Monte Carlo simulated annealing program to
study protein loop conformation. The program was shown to reproduce
loop conformation reliably for proteins. In order to study the environmental
effects on these peptides. We used the Monte Carlo simulated annealing
program to study the eight loop III sequences under the environment
of erabutoxin b. Since short chain neurotoxins are highly homologous,
it is reasonable to assume that they all take similar three-dimensional
structures. Our calculation shows that loop III in the NMR structure
of toxin from naja naja oxiana venom can be reproduced by simulation
with the protein environment of erabutoxin b.
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