Accardi L., Freudenberg W., Obya M. (Eds.) Quantum Bio-informatics IV: From Quantum Information to Bio-informatics
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Quantum
BiD-Informatics
IV
eds. L.
Accardi,
W. Freudenberg
and
M.
Ohya
© 2011
World
Scientific
Publishing
Co.
(pp
.
461-467)
THE PREDICTION OF BOTULINUM TOXIN STRUCTURE
BASED ON
IN
SILl
CO
AND
IN
VITRO ANALYSIS
TOMONORI SUZUKI AND SATORU MIYAZAKI
Department 0/ Medicinal
and
Life Science, Faculty 0/ Pharmaceutical Sciences, Tokyo
University o/Science,
2641 Yamazaki, Noda 278-8510, Japan
Many
of
biological system mediated through protein-protein interactions. Knowledge
of
protein-protein complex structure is required for understanding the function. The
determination
of
huge size and flexible protein-protein complex structure by
experimental studies remains difficult, costly and five-consuming, therefore
computational prediction
of
protein structures
by
homolog modeling and docking studies
is valuable method. In addition, MD simulation is also one
of
the most powerful methods
allowing to see the real dynamics
of
proteins. Here, we predict protein-protein complex
structure
of
botulinum toxin to analyze its property. These bioinformatics methods are
useful
to
report the relation between the flexibility
of
backbone structure and the activity.
1.
Introduction
In the post genome era, since it
is
generally assumed that function
of
a protein
is
closely linked to its three-dimensional structure, many research groups work on
protein structure determination by X-ray crystallography or solution nuclear
magnetic resonance (NMR). There are more than
68,000 structures registered in
Protein Data Bank (PDB)
as
of
2010. However, since mu1tidomain proteins and
complex proteins are often difficult to crystallize and many are too large for
NMR structure determination, the rate
of
structure determination
is
still low
compared with sequence determination.
On the other hand, a number
of
computational methods have been developed for the prediction
of
protein
structures and interactions from genomic and structural information. We have
been studying the structures
of
botulinum toxin, which
is
large multimeric
protein complex consisting
of
several different components. Some
of
the
component and complex structures have not yet been determined. Here, we
describe the prediction
of
botulinum toxin and related protein structures
by
the
computational methods.
Clostridium botulinum
is
anaerobic bacterium; which produces seven
distinct serotypes (A-G)
of
neurotoxins (BoNT; 150 kDa) [1]. BoNT
is
461
462
synthesized
as
a single chain and associates with non-toxic proteins in culture
supernatants. These include the non-toxic non-hemagglutinin (NTNHA;
130
kDa) and three types
of
hemagglutinin (HA) subcomponents, HA-70, HA-33
and HA-17
(70,
33
and
17
kDa, respectively), forming a large toxin complex
(TC) held together by non-covalent binding. We analyzed the 3D structure and
function
of
TCs
of
serotypes C and
D.
In the case
of
serotype C and D, 3D
structures
of
HA-33
(C
and D), HA-17 (D) and HA-70 (C) have been
determined by X-ray crystal diffraction. However, other structures are still
unknown.
So
far, we have reported the model structure
of
TC based on in vitro
experimental data (Fig.
1)
[2, 3], some interaction region
[2]
and predicted 3D
structures
of
BoNT, trypsin like protease (TLP) and
TLP/BoNT
complex (Fig.
2) [4]. Thus, determination or predict
of
the individual component
of
TC were
almost accomplished. In this work, we predicted 3D structures
of
NTNHA and
HA-70 produced by
C.
botulinum serotype
D.
Figure
1.
Schematic
model of
Botulinum
toxin complex.
The
toxin complex consists of
BoNT (red),
NTNHA
(green), HA-70 (yellow), HA-33 (blue)
and
HA-17 (cyan).
463
Figure
2.
Predicted
structures
of
serotype
C
BoNT
(A),
TLP
(B)
and
BoNT/TLP
complex
(C).
2. Modeling of NTNHA structures
No structures
of
NTNHA have been determined by X-ray diffraction
crystallography
as
yet. The NTNHA sequence has about 40% sequence
homology
to
the BoNT and tetanus neurotoxin (TeNT). The structures
of
BoNT
464
and C-terminal region
of
TeNT have been determined [5,
6,
7]. Thus, we
predicted C-terminal region
of
NTNHA structure. The modeled structures
of
NTNHA produced by serotype D was constructed, using the program Discovery
Studio v1.7 (Accelrys Software Inc., San Diego, CA,
USA). For modeling
of
serotype D NTNHA, serotypes A (PDB ID: 3BTA) and B (lEPW) BoNTs and
TeNT (lDIW) were used
as
template structures. The commonly conserved
regions present
in
the NTNHA and template structure were determined by
sequence homology and secondary structure alignment (Fig. 3). Secondary
structure prediction
of
the NTNHA was carried out using PSI-PRED [8].
Validation
of
the models was carried out using Ramachandran plot calculation
computed with the Swiss-PdbViewer (available at
http://swissmodel.expasy.org/
spdbvl)afterstructureminimization
.
In
Ramachandran plot space, over 80%
of
residues were in the favored region.
As a result
of
modeling, C-terminal region
of
NTNHA were predicted
(Leu837 to Ser1191) (Fig. 4A). There
is
gap in sequence alignment
ofNTNHA
and neurotoxins, and most
of
these gap regions correspond
to
long loop region
of
neurotoxins (Fig. 4B). The result suggests, the NTNHA structure
is
more
compact than neurotoxin structures.
.--
--
Figure
3.
Sequence
alignment
of
NTNHA
and
template
structures
(C·terminal
domain
of
neurotoxins).
465
Figure
4.
(A)
Predicted
C-terminal
region
of
NTNHA
structure.
(B)
Superimposed
structure
with
template
structures.
Yellow; NTNHA, white; BoNT/A, blue;
BoNTlB
and
pink; TeNT.
466
3. Modeling of HA-70
structure
For modeling
of
serotype D HA-70 structure, serotype C HA-70 structure (PDB
ID: 2ZS6) was used
as
template structures [9]. Sequence homology between
serotype C and D
HA-70
is
over 90%, however serotype C HA-70 structure
contains deleted region. To fill the deleted region, we used the partial structure
of
integrin
as
template (PDB ID: 3FCS) [10]. In Ramachandran plot space, over
80%
of
residues
of
predicted HA-70 were in the favored region. The single
chain
HA-70
is
nicked by TLP at specific site. The HA-70
is
thereby split into a
dichain structure [11]. As a result
of
prediction
of
intact HA-70 structure,
nicking site was exposed on the molecular surface, which
is
likely
to
be
specifically attacked by
TLP (Fig. 5).
We have predicted the BoNT, NTNHA (only C-terminal region) and
HA-70
of
serotype
D.
The structure
of
HA-33/HA-17 has been determined by X-ray
crystallography analysis [3]. And some interaction regions between
TC
components have been estimated by in vitro experiments [2, 12]. To clarify the
botulinum
TC structure, we attempt
to
determine the complete structures
of
subcomponents and interaction sites.
Figure
5.
(A)
Predicted
serotype
D HA-70
structure.
(B)
Close·up view
of
nicking
site.
467
Acknowledgments
The authors thank Drs.
T.
Ohyama,
T.
Watanabe and
K.
Niwa, Tokyo
University
of
Agriculture, for their in vitro experiments.
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This page intentionally left blankThis page intentionally left blank
Quantum
Bio-Informatics
IV
eds. L.
Accardi,
W .
Freudenberg
and
M.
Ohya
© 2011
World
Scientific
Publishing
Co
. (pp. 469- 490)
ON
THE
MECHANISM
OF
D-WAVE
HIGH
Tc
SUPERCONDUCTIVITY
BY
THE
INTERPLAY
OF
JAHN-TELLER
PHYSICS
AND
MOTT
PHYSICS
H.
USHIO
Tokyo
National
College
of
Technology,
1220-2
Kunugida-chou,
Hachioji
193-0997
,
Japan
E-mail:ushio@tokyo-ct.ac.jp
S.
MATSUNO
Shimizu
General
Education
Center,
Tokai
University,
3-20-1
Orido
Shimizu-ku,
Shizuoka
424-8610, Japan,
E-mail:
smatasuno@scc.u-tokai.ac.jp
H.
KAMIMURA
Department
of
Applied
Physics,
Tokyo
University
of
Science,
1-3
Kagurazaka,
Shinjuku-ku,
Tokyo
162-8601, Japan,
E-mail:
kamimura@rs.kagu.tus.ac.jp
In
the
present
paper
we will discuss
two
important
roles
of
the
interplay
of
Jahn-
Teller physics
and
Mott
physics.
One
is
the
small
Fermi
surface.
The
"Fermi
arcs"
observed
in
ARPES
should
be
one
of
the
edges
of
small
Fermi
pockets,
based
on
the
Kamimura-Suwa
model
(K-S
model).
This
prediction
is
consistent
with
ARPES
results
by
Tanaka
et
al.
Another
is
the
mechanism
of
superconductivity
in
cuprates.
This
can
be
explained
by
the
interplay
of
strong
electron-phonon
interactions
and
local
AF
order.
It
is
shown
that
the
characteristic
phase
difference
of
wave
functions
between
u
p-
and
down-spin
carriers
in
the
presence
of
the
local
AF
order
leads
to
the
superconducting
gap
of
d
x
2_y2
symmetry
even
in
the
phonon-involved
mechanism.
1.
Introduction
In
1986 Bednorz
and
Miiller discovered high
temperature
superconductiv-
ity
in copper oxides
with
motivation
that
higher
Tc
could be achieved
by
combining
Jahn-
Teller
(JT)
active
eu
ions
with
the
structural
complex-
ity
of layer-type perovskite oxides.
1
Their
idea gets
the
essential
point
in
considering
the
mechanism of high
Tc
superconductivity.
469