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Cite This: ACS Omega 2018, 3, 11497−11503 http://pubs.acs.org/journal/acsodf

Effects of Size and Functionalization on the Structure and Properties

of Graphene Oxide Nanoflakes: An in Silico Investigation
Enxi Peng, Nevena Todorova, and Irene Yarovsky*
School of Engineering, RMIT University, GPO Box 2476V, 3001 Melbourne, Victoria, Australia
*
S Supporting Information

ABSTRACT: Graphitic nanoparticles, specifically, graphene oxide

(GO) nanoflakes, are of major interest in the field of nanotechnology,
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with potential applications ranging from drug delivery systems to

energy storage devices. These applications are possible largely because
of the properties imparted by various functional groups attached to the
GO surface by relatively simple production methods compared to
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pristine graphene. We investigated how varying the size and oxidation

of GO flakes can affect their structural and dynamic properties in an
aqueous solution. The all-atom modeling of the GO nanoflakes of
different sizes suggested that the curvature and roughness of relatively
small (3 × 3 nm) GO flakes are not affected by their degree of
oxidation. However, the larger (7 × 7 nm) flakes exhibited an increase
in surface roughness as their oxidation increased. The analysis of water
structure around the graphitic nanoparticles revealed that the degree of
oxidation does not affect the water dipole orientations past the first hydration layer. Nevertheless, oxygen functionalization
induced a well-structured first hydration layer, which manifested in identifiable hydrophobic and hydrophilic patches on GO.
The detailed all-atom models of GO nanoflakes will guide a rational design of functional graphitic nanoparticles for biomedical
and industrial applications.

1. INTRODUCTION ity,2,6 enzyme inhibitors, and drug delivery vehicles.2,6−9 More

Graphitic nanomaterials have been a highly topical area of
research in the past decade, with an array of possible
applications ranging from drug delivery to biosensing and
prevention of biofouling.1,2 In recent years, graphene oxide
(GO), the surface-functionalized cousin of pristine graphene
(PG), has become widely recognized as the more accessible
nanomaterial relative to PG. GO is chemically synthesized
using Hummer’s method,3 which was refined by Lerf and
Klinowski et al.,4 where a mixture of KMnO4 and concentrated
H2SO4 is reacted with graphite to produce GO with the
chemical composition of C10O1(OH)1(COOH)0.5. The
distribution of functional groups comprises two epoxy groups,
two hydroxyl groups on both sides of the basal plane, and one
carboxyl group on the edge for every 20 carbon atoms. This
chemical structure allows GO flakes to be easily synthesized,
transported, and handled, relative to native PG flakes.
Graphene can also be functionalized with various types of
functional groups other than oxygen through both covalent
and noncovalent modifications.5 Because of the presence of the
large and highly functionalized surface, GO allows for
noncovalent interactions with biological molecules via electro-
statics, π−π stacking, and hydrogen bonding. This function-
alization also contributes to the desirable optical, mechanical,
and electrical properties2 of GO, which are exploited in
biomedical applications, for example, biosensors for the
detection of biomolecules with high sensitivity and selectiv-
recently, several studies identified the potential of these
nanoparticles to mediate the formation of amyloid protein
fibrils, known for their implications in debilitating neuro-
degenerative diseases.10−12 In this paper, we explore the
structural modeling of the GO nanoflakes for subsequent
applications in controlling the amyloid fibril formation.
Computational modeling provides direct access to the
structural characterization of nanomaterials complementary
to experiments.13,14 Several computational studies focused on
the structure of GO nanoparticles, mostly with the aim of
improving the mechanical properties of this nanomaterial.15−17
In particular, Khoei et al. demonstrated that increasing the
proportion of the oxygen-containing functional groups also
increased the C−C bond length of the hexagonal lattices of
graphene, causing a distortion in the hexagonal lattice.15 This
resulted in the alteration of the mechanical properties of the
material such as shear modulus and elastic constants. Wei et al.
modeled the wetting properties of GO relative to PG and
found that the oxidized regions contributed to the spreading of
water droplets across the surface.16 Controlling the proportion
of the oxygen functionality can thus be used for modulating the
water behavior on the GO surfaces. These studies suggest that
Received: May 1, 2018
Accepted: September 7, 2018
Published: September 20, 2018

© 2018 American Chemical Society 11497 DOI: 10.1021/acsomega.8b00866

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the degree of oxidation has a significant effect on the
mechanical and wetting properties of the graphitic flakes. In
addition, several recent theoretical studies investigated the
behavior of GO sheets and GO nanoflakes in the presence of
biomolecules and solvents.7,18−25 These studies indicated that
the highly functionalized GO interacted most favorably with
the biomolecules via hydrogen bonding, whereas the GO with
low oxygen functional group densities prevalently interacted
through π−π stacking.16,17 The theoretical studies utilized
various modeling approaches to simulate the bonded and
nonbonded interatomic interactions of GO. The most
common approach for modeling GO7,16,19,22,24 is to use the
LJ sp2 carbon potentials from AMBER96, the bond angle
parameters from CHARMM27,26 and all other interaction
parameters from the OPLS-AA force field.27 Although this
approach may be adequate to model simple homogeneous
systems, it has not been validated for modeling GO
interactions with biomolecules. In addition, the CHARMM
force field was used more recently by Bansal et al. for the
modeling of aqueous GO dispersion.28 This study concluded
that the functional groups on the GO surfaces prevented the
GO aggregation in water through strong repulsive forces,
which were shown to increase with an increasing concentration
of functional groups. The analysis of hydrogen bonding data
also indicated that both epoxy- and hydroxyl-functionalized
GO surfaces were stabilized via the intra- and interlayer water-
mediated H-bonds.28 Similarly, Tang et al.18 highlighted that
the type of functional group, the oxygen content, and the initial
distance between the GO flakes all play a significant role in the
aggregation kinetics of GO nanoparticles.
Alternatively, the GO−biomolecular complexes have been
simulated using material-orientated force fields such as
COMPASS,17,29,30 originally developed for modeling organic
(polymer) interfaces with metal oxides. For example, Rahmani
et al. utilized the COMPASS II force field to model the
adsorption of various amino acids on GO surfaces.29 Their
study concluded that the surface functionalization of GO
disrupted the π−π stacking between the surface and the
aromatic residues of the amino acids. Class II force fields are
generally computationally expensive, as the functional form of
the Hamiltonian includes anharmonic terms, such as quartic
stretching and quartic angle bending as well as a variety of
other important intramolecular coupling interactions.31 How-
ever, COMPASS has undergone limited development and
testing for biomolecular systems, and, as a result, the
computational cost and biomolecular force field deficiencies
do not generally justify its application to sampling complex
biological phenomena.
Unlike PG, GO is highly soluble in water; thus, its influence
on the surrounding water structure is one of the important
factors that will ultimately control its interactions with
biomolecules.32−35 As a result, it is important to understand
the mechanisms of interactions that govern the structure and
dynamic behaviors of the GO nanoflakes in an aqueous
environment. Moreover, as demonstrated by previous stud-
ies10,11,20,36 the nanoparticle size, functionalization, and
curvature play an important role in the biomolecular
recognition and protein adsorption onto the surface of the
nanoparticle. Despite the noteworthy research efforts on GO,
there is a gap in understanding the interconnection between
the size and the degree of oxidation of the GO nanoflakes and
their physical and (bio)chemical properties. To exploit the
unique properties of the GO particles in biomedicine, it is
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crucial to reveal how these properties influence the GO
interactions with the environment, primarily the behavior of
the surrounding solvent and biomolecules. This paper reports a
theoretical modeling investigation of the effects of GO
nanoflake size and degree of functionalization on the GO
surface structure, dynamics, and interactions in the aqueous
solution relevant to biological environments. The outcomes of
this study provide the atomistic insights needed for a rational
design of novel graphitic nanomaterials with a desired behavior
and an optimized and controlled function for biomedical
applications.
2. RESULTS AND DISCUSSION
2.1. Surface Roughness and Flexibility of Graphitic
Nanoflakes. The shape and curvature of nanoparticles were
highlighted to be a major factor implicated in protein
binding.36 The average surface roughness (or curvature) of
all the nine graphitic models is shown in Figure 1, indicating a
Figure 1. Average roughness of graphitic nanoflakes as a function of
size and degree of oxidation.
general trend of the average roughness increase with the
increased size and degree of functionalization of the graphitic
flakes. For the 3 nm flakes, there was a small increase (∼0.1
nm) in the surface roughness with increasing oxidation,
suggesting that the nanoparticles are too small for the
functional groups to induce the significant response in the
curvature. By contrast, the presence of oxygen-containing
groups in the larger (5 and 7 nm) rGO and GO flakes
increased the curvature of the nanoparticle approximately
twofold, compared to PG of the same size. Moreover, the 5 nm
flakes of rGO and GO had a negligible difference (within the
standard deviation) in their surface roughness, indicating that
the curvature in rGO is largely induced by the edge functional
groups. Overall, the 7 nm flakes exhibited the most significant
increase in surface roughness as the degree of oxidation
increased, with the PG measuring roughness of 0.9 ± 0.05 nm,
and rGO and GO of 1.2 ± 0.07 nm and 1.6 ± 0.13 nm,
respectively.
To understand the relationship between the measured
surface roughness and the flexibility of the particle, the root-
mean square fluctuation (RMSF) of individual atoms in each
graphitic flake was calculated for the final 50 ns of the
simulated trajectories. The average RMSF values are presented
in Figure 2, using the color scale ranging from 1 to 10. The
blue-colored areas indicate a high RMSF, whereas the red-
colored areas indicate low fluctuations. The ratio of the stiff
(red) to mobile (blue) areas is presented below each plot. For
all the 3 nm flakes, high fluctuations were observed at the
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dynamic differences of GO could affect protein folding and

Figure 2. Average fluctuations of individual atoms in each graphitic
nanoflake. The color scale represents the normalized RMSF values.
The numbers below each plot indicate the ratio of stiff to mobile
surface areas.
adsorption. Several studies have investigated the properties
that contributed toward biomolecule adsorption to nano-
particles. For example, works by Hughes and Walsh had
emphasized that exploiting interfacial water structuring was key
for understanding selective behavior in peptides binding to
multifaceted gold nanoparticles and graphene.33,37 It was also
highlighted that a highly structured water layer provides
favorable conditions for peptide adsorption at the nano-
structured surfaces. Another study uncovered that intermittent
interactions with water can mediate protein adsorption on
surfaces, whereas longer lasting interactions control the
diffusion of water around the adsorption sites.34,38 Another
study highlighted that the hydration shells of unfolded proteins
are more compressible than those on the folded ones
contributing to protein denaturation because of pressure.39
Thus, by understanding the hydration patterns around the
graphitic nanoparticles, we can help elucidate how they could
influence the binding motifs of proteins on the nanoparticle
surface.1,32,40−42
To better understand the water molecule behavior around
the graphitic nanoparticles, GO−water radial distribution
function (RDF) and water dipole analyses were performed.
Figure 3 shows the solute (O)−water (H) RDFs for the rGO
and GO flakes. For the PG flakes, the RDF was calculated
between the carbon atoms and the water molecules. In Figure
3A, a formation of hydration shells around the rGO and GO
flakes can be clearly identified by two characteristic peaks. The

corners of each flake, while the inner area of the flakes

remained stable or less dynamic. This indicates that the minor
variances in roughness between the 3 nm graphitic flakes are
mostly attributed to the edge fluctuations. The 3 nm rGO
sheet has significantly more stiff areas within the sheet as its
stiff/mobile area ratio is 1.1, compared to 0.53 and 0.43 in the
PG and GO flakes, respectively. This is likely due to the lack of
edge functional groups to induce higher fluctuations around
the edges as observed in the GO flakes, combined with the
smaller size of the flake where oxidation stabilized the inner
areas.
Increases in fluctuations were also observed around the
edges of the 5 nm graphitic flakes, with reduced fluctuations
around the center of the flakes. Figure 2 shows that the
introduction of functional groups reduces the flexibility of the
rings, evidenced by less fluctuations exhibited by the densely
functionalized areas. This oxidation-induced rigidity is the
main contributor to the variances in roughness seen between
different flake sizes. This effect was also observed by Khoei and
Khorrami15 as discussed previously, where an increase in
oxidation agents in graphene sheets leads to decreased elastic
constants. The RMSF results for the 7 nm flakes revealed
relatively larger areas of low fluctuations manifesting in the
overall reduced dynamics compared to the smaller flakes.
Therefore, it can be suggested that, for larger flakes, it is the
increased concentration of oxygen functional groups on the
graphitic surface that induced the localized structural rigidity.
This also played an important role in the increased surface
roughness, whereas the edge effects play a dominant role in the
roughness and dynamics of the small size flakes.
2.2. Water Structure and Dynamics. Investigating the
behaviors of water around the graphitic flakes can shed light on Figure 3. RDFs between water and graphene functional groups on
how water structuring resulting from chemical, structural, and differently sized GO flakes: (A) 3, (B) 5, and (C) 7 nm.

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first water shell for all the three flake sizes (3, 5, and 7 nm) can
be found around 0.15−0.25 nm from the nanoparticle surface,
with a second water shell forming between 0.25 and 0.35 nm.
The RDF results for the PG flakes identified the first hydration
shell at 0.25−0.3 nm from the nanoparticle because of
graphene’s hydrophobic nature of hydration.43 For both rGO
and GO flakes, the amplitude of each RDF peak is consistent
between the two flake sizes for both water shells. This suggests
that because of the low roughness and smaller hydrophobic
areas on the 3 nm rGO and GO flakes, there is higher density
of water molecules in the first water shells around these
nanoparticles. A small peak indicating a possible third water
layer between 0.5 and 0.7 nm can be seen for the 3 nm rGO
and GO flakes. However, this characteristic third peak is not
visible for the 5 and 7 nm flakes, as after 0.6 nm, the RDF
approaches that of bulk water. It is important to note that the
positions of the first two hydration shell peaks do not change
with the flake size; however, the magnitude does. In Figure
3B,C, the RDF for GO is significantly higher than for rGO,
which suggests that as the flake size and the degree of
functionalization increase, more water molecules are packed
into the first hydration shell. These results demonstrate that
the graphitic nanoflakes can be tailored to have different
curvatures and provide varying degrees of affinity toward water,
which can be exploited to mediate protein binding.
Figure 4. Average SASAs for the GO models expressed in terms of
Furthermore, water dipole analysis was performed for all water coverage fraction (%). A representative frame was selected from
simulation systems in order to determine how surface the equilibrium portion of the molecular dynamics (MD) trajectories
functional groups affect water orientation in each of the to visualize the first hydration layer.
observed hydration layers (see figures in the Supporting
Information). The dipole orientation of each water molecule
within each hydration layer and bulk solution was calculated layer is approximately ∼88 ± 1−2% across all the three flake
(measured relative to Z-axis). For the 3 and 5 nm particles, the sizes. As the degree of functionalization decreased to rGO and
dipole angle distributions of the first and second hydration PG, a significant drop in water coverage was observed.
layers as well as the bulk water all have a characteristic bell Specifically, the water coverage range was ∼60−70 ± 3−4%
shape. The peak of this bell curve rests around a 90° angle, for rGO and ∼42−53 ± 3−6% for PG. Interestingly, the
indicating that the majority of water molecules in these increased size did not increase the coverage. In fact, at a lower
hydration layers are not orientationally influenced by the functionalization, the degree of water coverage decreased with
surface functional groups of the smaller (3 and 5 nm) graphitic an increase in the flake size. The 3 nm rGO flake had an
flakes. By contrast, the water dipole angle distribution for the 7 average coverage of 71 ± 4%, which reduced to 59 ± 3% for
nm GO flake exhibited a rougher profile compared to the the 7 nm flake. A similar trend was also observed for the PG
smaller nanoflakes with notable peaks between 40°−75° and flakes, with 53 ± 3% and 42 ± 6% coverage fractions for 3 and
120°−160°. This suggests that the highly oxidized larger flakes 7 nm flakes, respectively. This decrease in water coverage can
induce water dipole orientation because of the significant be attributed to the significant increases in the surface area of
number of water interactions with hydrophilic functional hydrophobic patches on either side of the basal plane. This
groups on the flake surfaces and edges. However, this induced observation explains the aggregation behavior illustrated by
dipole orientation does not extend past the first water layer as Bansal et al.,28 where repulsive interactions between the flakes
observed in Figure S3. Although no induced dipole orientation increased with increasing functionalization. As a result, more
was seen across any of the simulated flakes below the 7 nm water was displaced from the surface of less functionalized
size, we observed an increase in bound water with an flakes allowing for smaller interlayer spacing to occur, driven
increasing degree of oxidation across all nanoparticle sizes, in by hydrophobic surface association. As highlighted by Tang et
line with the RDF results shown in Figure 3. Overall, it can be al.,18 the initial distance between the graphitic flakes plays an
suggested that for the GO nanoflakes studied here, the surface important role in their aggregation velocity. Therefore, the
functionalization does provide interaction sites for water; increased fraction of hydrophobic patches observed here for
however, these interactions are not sufficient to induce dipole less functionalized GO flakes can explain the experimentally
orientation effects past the first hydration layer and into bulk observed aggregation behaviors.18,28
water.
2.3. Solvent-Accessible Surface Area. The solvent- 3. CONCLUSIONS
accessible surface area (SASA) of each graphitic model was The MD simulation characterized the surface roughness of a
also calculated and expressed in terms of water-covered surface series of nanoscale PG flakes with various degrees of
fractions (%), as illustrated in Figure 4. It can be clearly seen functionalization, as well as the characterized water behavior
that as the degree of functionalization increased, the around these graphitic nanoparticles. Our results showed that
percentage of water coverage also increased. For GO flakes, the roughness of the GO flakes increases with their size and
the average covered fraction of the surface by the first water degree of functionalization. In addition, increasing the surface
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functionalization greatly increased the GO affinity to water,
increasing the ratio of hydrophilic to hydrophobic surface areas
as the degree of oxidation increased. However, the affinity for
water did not cause any water structuring past the first water
layer, with the effects of functional groups on water dipole
alignment only evident for the 7 nm GO flake. The findings of
this study contribute to understand the structure dynamics and
hydration of graphitic nanoparticles. The ability to control the
shape and hydration level of the graphitic nanoparticles can
lead to the design and optimization of nanomaterials to
modulate the protein binding in biomedical applications.
4. METHODOLOGY
4.1. Graphitic Nanoflake Models. The GO flakes of
different sizes and degrees of oxidation were built using the
BIOVIA Materials Studio software suite.44 In order to model
GO with varying functionalities, a script was generated to
randomly assign functional groups to a PG surface of [3 × 3]
nm, [5 × 5] nm, and [7 × 7] nm in size (herein simply
denoted as 3, 5, and 7 nm particles for ease of discussion) in
accordance with the chemical composition described in the
literature.4 These GO flake sizes are consistent with the
applications of graphitic particles in a biologically relevant
environment, where size compatibility is required to study the
peptide/protein adsorption on the particle surface. We ensured
that the induced randomness in the functional group
distribution did not violate any physicochemical principles.45,46
Initial geometry optimization was then performed using the
COMPASS II47 force field to ensure no steric clashes existed.
A total of three oxidation states of GO were created for each
nanoflake size: PG, reduced GO (rGO with the C/O ratio of
10:1), and GO (GO with the C/O ratio of 5:1). The degree of
oxidation used in this study to model the GO and rGO
nanoflakes are in line with the experimentally determined
ratios of 4:1 for GO48 and 10:1 for rGO.49 This generated nine
different graphene nanoflake models for subsequent simu-
lations in an explicit solvent (Figure 5).
The bonded interactions for GO were taken from the
CGenFF force field,50,51 which utilizes an atom-typing
approach whereby the parameters are assigned through
analogies with an existing database of molecules. This
approach was applied in recent studies investigating the
accuracies of force fields for modeling the chemical and
physical properties of GO.52 Such a method of parameter-
ization avoids the need to combine the parameters from
various other force fields.7,19,22,24 It is important to recognize
that when the interactions between a nanoparticle and the
biological molecules are of interest, a consistent set of
interatomic potentials needs to be used to model each
individual system component as well as the entire nano−bio
complex.14,53−56 With this in mind, the choice of CGenFF,
which is compatible with the CHARMM group of biological
force fields, is appropriate for applications to nano-biosystems
aimed as a follow-up of this work.57 In this study, the bonded
GO parameters from CGenFF were plugged into
CHARMM22* for all simulations. The QEq algorithm58 was
used to determine the partial atomic charges based on the
experimental zeta-potential of GO as measured by Konkena
and Vasudevan for GO at varying pH values.59 Specifically, the
zeta-potential of GO at neutral pH (−44 mV) was used, which
resulted in a total surface charge of −0.04 e/nm2, and
neutralized by counterions. The partial charges for PG and
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Figure 5. Model parameters investigated in this study.
rGO were equilibrated to produce a neutral particle, in line
with a standard simulation practice.24
4.2. Simulation Details. All simulations were performed
using the GROMACS 5.0.5 software package,60−62 using
classical MD with interatomic interactions parameterized as
described in the above section. The van der Waals and
electrostatic interactions were truncated at 1 nm with long-
range electrostatics calculated by the particle mesh Ewald
summation method.63 Each graphitic particle was suspended in
a cubic simulation box sufficiently large (allowing at least 1.5
nm separation between the particle and the edge of the box) to
prevent mirror image interactions. In vacuo energy mini-
mization was performed to eliminate any steric clashes using
the steepest descent algorithm. The simulation box was then
solvated with TIP3P water64 and another energy minimization
was performed. An MD simulation at a constant number of
particles, constant volume, and temperature (NVT ensemble)
was conducted for 1 ns to equilibrate the water molecules
around the graphitic nanoparticle. Following this, the MD
simulations were performed for 200 ns for each system under
the isothermal−isobaric conditions (NPT ensemble). The
constant pressure and temperatures were maintained via the
Berendsen barostat65 and v-rescale thermostat,66 respectively.
The LINCS algorithm61 was applied to constrain the bond
lengths to their equilibrium values, which allowed for a
simulation time step of 2 fs to be used.
4.3. Data Analysis. All analyses were carried out on the
final 50 ns of the simulated trajectory, with the convergence
being confirmed by the RMSD (within 0.3 nm) of the graphitic
structure and total energy reaching a plateau. The average
surface roughness for each graphitic system was measured
using the 10-point roughness method,67 where Z-axis
coordinates of every carbon atom relative to the starting
structure are used, ignoring the “out-of-plane” and diffusive
motion. The five maximum and five minimum values of the Z-
axis coordinates for each frame were then determined, and the
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difference between the average maximum and minimum values
was taken as the roughness measured of the flake at that
specific frame. Atomic RMSF analysis was performed on the
aligned trajectories (as described above) to determine the
effects of size and functionalization on the flake dynamics. In
addition, RDFs between water molecules and the functional
groups and carbon atoms, as well as water dipole analyses, were
utilized to better understand the water structuring around the
graphitic particles and its role in the observed curvature
patterns and dynamics of the GO flakes. The SASA of each
flake was measured using the VMD SASA analysis tool.68
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsome-
ga.8b00866.
Water dipole orientation analysis within the first two
hydration shells and bulk water for each flake size and
functionalization degree (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: irene.yarovsky@rmit.edu.au. Phone: +61 3 9925 2571
(I.Y.).
ORCID
Irene Yarovsky: 0000-0002-4033-5150
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
I.Y. acknowledges the Australian Research Council for financial
support under the Discovery Project scheme (DP140101888
and DP170100511). This research was undertaken with the
assistance of resources from the National Computational
Infrastructure (NCI), grant number (e87), the Pawsey
Supercomputing Centre, and Melbourne Bioinformatics,
Australia. Dr. Adam J. Makarucha and Dr. M. Harunur Rashid
are acknowledged for their guidance at the early stage of this
research.
■
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