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In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4
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4.1 Introduction
4.1.1 Environmental Chemical Causing Cancer
People are continuously exposed exogenously to varying amounts of chemicals that
have been shown to have carcinogenic or mutagenic properties in experimental
systems. Exposure can occur exogenously when these agents are present in food, air
or water, and also endogenously when they are products of metabolism or
pathophysiologic states such as inflammation. It has been estimated that exposure
to environmental chemical carcinogens may contribute significantly to the causation
of a sizable fraction, perhaps a majority, of human cancers, when exposures are
related to "life-style" factors such as diet, tobacco use, etc. A causative relationship
between exposure to aflatoxin, a strongly carcinogenic mold-produced contaminant
of dietary staples in Asia and Africa, and elevated risk for primary liver cancer has
been demonstrated through the application of well-validated biomarkers in
molecular epidemiology. These studies have also identified a striking synergistic
interaction between aflatoxin and hepatitis B virus infection in elevating
liver cancer risk. Use of tobacco products provides a clear example
of cancer causation by a life-style factor involving carcinogen exposure. Tobacco
carcinogens and their DNA adducts are central to cancer induction by tobacco
products, and the contribution of specific tobacco carcinogens (e.g. PAH and NNK)
to tobacco-induced lung cancer, can be evaluated by a weight of evidence approach.
Factors considered include presence in tobacco products, carcinogenicity in
laboratory animals, human uptake, and metabolism and adduct formation, possible
role in causing molecular changes in oncogenes or suppressor genes, and other
relevant data. This approach can be applied to evaluation of
other environmental carcinogens, and the evaluations would be markedly facilitated
by prospective epidemiologic studies incorporating phenotypic carcinogen-specific
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biomarkers. Heterocyclic amines represent an important class of carcinogens in
foods. They are mutagens and carcinogens at numerous organ sites in experimental
animals, are produced when meats are heated above 180 degrees oC for long
periods. Four of these compounds can consistently be identified in well-done meat
products from the North American diet, and although a causal linkage has not been
established, a majority of epidemiology studies have linked consumption of well-
done meat products to cancer of the colon, breast and stomach. Studies employing
molecular biomarkers suggest that individuals may differ in their susceptibility to
these carcinogens, and genetic polymorphisms may contribute to this variability.
Heterocyclic amines, like most other chemical carcinogens, are not carcinogenic per
se but must be metabolized by a family of cytochrome P450 enzymes to chemically
reactive electrophiles prior to reacting with DNA to initiate a carcinogenic response.
These same cytochrome P450 enzymes--as well as enzymes that act on the metabolic
products of the cytochromes P450 (e.g. glucuronyl transferase, glutathione S-
transferase and others)--also metabolize chemicals by inactivation pathways, and the
relative amounts of activation and detoxification will determine whether a chemical
is carcinogenic. Because both genetic and environmental factors influence the levels
of enzymes that metabolically activate and detoxify chemicals, they can also
influence carcinogenic risk. Many of the phenotypes of cancer cells can be the result
of mutations, i.e., changes in the nucleotide sequence of DNA that accumulate as
tumors progress.
These can arise as a result of DNA damage or by the incorporation of non-
complementary nucleotides during DNA synthetic processes. Based upon the
disparity between the infrequency of spontaneous mutations and the large
numbers of mutations reported in human tumors, it has been postulated that
cancers must exhibit a mutator phenotype, which would represent an early
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event in cancer progression. A mutator phenotype could be generated by
mutations in genes that normally function to guarantee genetic stability. These
mutations presumably arise via DNA damage by environmental or endogenous
agents, but it remains to be determined whether the acquisition of a mutator
phenotype is a necessary event during tumor progression ( Wogan GN et
al.,2004 ).
4.1.2 Prevention of Carcinogenesis by using Nanoparticles as a Scavenger
Nanotechnology, actually means the exploitation of the substances at their nano-
meter size, is expected to enhance the quality of life and economic development on
the global basis. Understanding of biological processes on the nanoscale level is a
strong driving force behind development of nanotechnology. Out of surplus of size-
dependant physical properties of nanomaterials like optical and magnetic effects
have been exploited for a number of biological/medical applications, eg: their use as
fluorescent biological labels, for the drug and gene delivery, for the detection of
pathogens, detection of proteins, Probing of DNA structure, in tissue engineering, for
the treatment of cancer by tumor destruction via heating (hyperthermia), for the
separation and purification of biological molecules and cells, in the contrast
enhancement of MRI, and phagokinetic studies etc. The list of applications of
nanomaterials to biology or medicine is ever escalating. Recently some of the
nanoparticles have been employed in scavenging the high molecular weight PAHs
from the contaminated soils (Karnchanasest and Santisukkasaem, 2007). Amphiphilic
polymer nanoparticles have been used as nano-absorbent for pollutants in aqueous
phase (Jin- Kie S him et al.,2007).
The scavenging capacities of the nanoparticles for PAH and other toxicants could
probably be attributed to their higher affinity towards the xenobiotics. The structural
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properties and surface chemistry of nanoparticles are the players, further, extremely
high surface area to volume ratio results in multiple enhancements of such
properties.
4.1.3 Nanoparticles (TiO2) have capacity to efficiently reduces the harmful
compounds -
TiO2 is biological Inert but in ultrafine form and in high conc. TiO2 causes the fibrosis
in tissues which may lead the cancer . In 2006, the International Agency for Research on
Cancer (IARC) reviewed the carcinogenic risk of TiO2 concluding that it is “possibly
carcinogenic to humans” (Group 2B) based primarily on studies in rats indicating lung
tumors. However, the results from four large human epidemiology studies involving more
than 40,000 workers in the titanium dioxide industry at manufacturing locations in North
America and Europe indicate neither association with an increased risk of lung cancer nor
with any other adverse lung effects.
Inhalation exposures to TiO2 in rats can result in lung effects and lung tumors. It is
generally recognized that the rat is uniquely sensitive to the effects of “lung overload”,
with the production of chronic lung inflammation and subsequent lung fibrosis and
tumor formation; a process not observed in other species including humans. The IARC
conclusion was based on studies that involved rat “lung overload” effects. But in low
and definite conc., UltraFine TiO2 significantly reduced the harmful compounds from
the cigarette smoke (Qixin Deng et al., 2011).
The scavenging capacities of the nanoparticles for PAH and other toxicants could
probably be attributed to their higher affinity towards the xenobiotics. The structural
properties and surface chemistry of nanoparticles are the players, further, extremely
high surface area to volume ratio results in multiple enhancements of such properties.
Cigarette smoke (CS) is a complex aerosol containing more than 2000 chemical
constituents, which are present in both particulate and vapour phase. The former is
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composed primarily of tar, nicotine and water. Tar contains various toxic or
carcinogenic chemicals such as polycyclic aromatic hydrocarbons (PAHs) and
tobacco-specific nitrosamines (TSNAs), even a trace amount of PAHs or TSNAs are
able to cause serious health risk.
Titanate nanosheets (TNS) and Titanate Nano Tubes (TNT) have also been
synthesized and then used as additives for removing harmful compounds in CS for
the first time (add Reference). After TNS and TNT were introduced into cigarette
filter, a great range of harmful compounds including nicotine, tar, ammonia,
hydrogen cyanide, selected carbonyls and phenolic compounds can be reduced
efficiently. Interestingly, TNT exhibits highly efficient reduction capability for the
most of the harmful compounds. This might be related to the intrinsic properties of
TNT (Qixin Deng et al., 2011).
Hence, we have followed a methodology to compare the binding efficiency of
nanoparticles and cigarette smoke carcinogens. The molecular interactions have been
accomplished using PatchDock server and interestingly got desirable results for our
hypothesis.
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4.2 Materials & Methods
Minimum system Requirement for the project is:
1) Supported Operating Systems
Discovery Studio Visualizer is supported on the following operating systems:
Microsoft® Windows XP Professional, SP2 and SP3
Microsoft Windows Vista, Business and Enterprise Editions, SP1
Red Hat® Enterprise Linux® 4.0, Updates 4-7
Red Hat Enterprise Linux 5, Retail, Updates 1-2
SUSE® Linux Enterprise 10 (SP2)
2) Processor and RAM Requirements
Processor: An Intel-compatible ≥2 GHz is required.
RAM: A minimum of 2 GB of memory for the visualizer.
3) Disk Space Requirements
A standard installation of Discovery Studio Visualizer requires 272 MB of disk space on
Windows and 454 MB on Linux.
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4) Software:
Accelrys discovery studio visualizer 2.5 (Designing of crystal structure, visualizing
and manipulating protein and crystal 3D structures)
PatchDock (Docking server)
Open Babel (File converter)
An Internet Browser and valid internet connection.
After studying the anatase crystal structure, we found that Accelrys Discovery studio
would be the most suitable software for the designing of TiO2 anatase crystal structure.
4.2.1 Method for Designing Crystal Structure
From the start menu,goto the all programs option and select the Accelrys
Discovery Studio 2.5 program.
Now goto file menu >> New >> Molecule Window.
A black sub window / tab will open up. Goto the Structure menu >> Crystal cell
>> Create cell.
A Crystal cell outline will appear in the black window in select mode (yellow
colour).
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Figure 4.1 Crystal Cell Outline
Now again goto Structure menu >> Crystal cell >> Edit Parameters…. A small
dialog box of Crystal Builder with 4 tabs will pop up.In the first tab, i.e. of Cell
parameters, edit the crystal lengths(A, B and C) and angles(alpha, beta and
gamma) according to the anatase lattice parameters,i.e.,
A = B = 3.785.
C = 9.514.
Alpha = beta = gamma = 90.
Now under the space group tab select the “I41/amd” space group and origin as
“origin-1 choice: 1”, and calculate the lattice positions of Ti atoms by the help of
the formulae given under positions in the space group tab.
The calculated positions are:-
1) 0, 0, 0
2) 0.5, 0.5, 0.5
3) 1, 0.5, 0.25
4) 0.5, 1, 0.75
5) 0.5, 0, 0.25
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6) 0, 0.5, 0.75
7) 0.5, 0.5, 0.5
8) 1, 1, 1
9) 1, 0.5, 0.75
10) 0.5, 0, 0.25
11) 0, 1, 1
12) 0.5, 0.5, 0.5
13) 0.5, 0.5, 0.5
14) 1, 0, 0
15) 0.5, 1, 0.75
16) 0, 0.5, 0.25
17) 0.5, 0.5, 0.5
18) 0, 0, 1
19) 0.5, 1, 0.75
20) 1, 0.5, 1.25
21) 0, 0.5, -0.25
22) 0.5, 0, 0.25
23) 1, 1, 0
24) 0.5, 0.5, 0.5
25) 0.5, 0, 0.25
26) 1, 0.5, -0.25
27) 0.5, 0.5, 0.5
28) 0, 1, 0
29) 1, 0, 1
30) 0.5, 0.5, 0.5
31) 0, 0.5, 1.25
32) 0.5, 1, 0.75
These are the 32 Wyckoff positions of the I41/amd space group. These are pre defined
positions,which were calculated using the general formulae for different wycoff
positions,
1. x, y, z
2. -x+1/2, -y+1/2, z+1/2
3. -y, x+1/2, z+1/4
4. y+1/2, -x, z+3/4
5. -x+1/2, y, -z+3/4
6. x, -y+1/2, -z+1/4
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7. y+1/2, x+1/2, -z+1/2
8. -y, -x, -z
9. -x, -y+1/2, -z+1/4
10. x+1/2, y, -z+3/4
11. y, -x, -z
12. -y+1/2, x+1/2, -z+1/2
13. x+1/2 , -y+1/2, z+1/2
14. -x, y, z
15. -y+1/2, -x, z+3/4
16. y, x+1/2, z+1/4
17. x+1/2, y+1/2, z+1/2
18. -x+1, -y+1, z+1
19. -y+1/2, x+1, z+3/4
20. y+1, -x+1/2, z+1.250000
21. -x+1, y+1/2, -z+1.250000
22. x+1/2, -y+1, -z+3/4
23. y+1, x+1, -z+1
24. -y+1/2, -x+1/2, -z+1/2
25. -x+1/2, -y+1, -z+3/4
26. x+1, y+1/2, -z+1.250000
27. y+1/2, -x+1/2, -z+1/2
28. -y+1, x+1, -z+1
29. x+1, -y+1, z+1
30. -x+1/2, y+1/2, z+1/2
31. -y+1, -x+1/2, z+1.250000
32. y+1/2, x+1, z+3/4
Considering x, y, z to be complementary with -x, -y, -z, i.e., here considering x = y = z = 0
and -x = -y = -z = 1.here the minus sign indicates the complementary function.
Note: fractional co ordinate = Actual length along an axis
Total length of a unit cell along that axis
These are the positions (fractional co ordinates) of Titanium. Now according to
the bond angle and bond length the corresponding Oxygen co ordinates are
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calculated. For faster calculation write a program in C to calculate the co
ordinates of Oxygen. The program which I have written is:
/*A program for calculation of the fractional co-ordinates of oxygen in anatase*/
/*Author QMSJ date:17/03/2012*/
#include<stdio.h>
#include<conio.h>
#include<math.h>
void main()
{
float xa,xb,xc,ya,yb,yc,za,zb,zc,x,y,z=0;
clrscr();
printf("Enter the values of the fractional co-ordinates(x,y,z):");
scanf("%f %f %f",&x,&y,&z);
if(x<1)
{
xa=x + (1.937*cos(12.308))/3.785;
xc=z + (1.937*sin(12.308))/9.514;
xb=0;
}
if(y<1)
{
ya=0;
yb=y + (1.937*cos(12.308))/3.785;
yc=z - (1.937*sin(12.308))/9.514;
}
if(z<1)
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{
za=0;
zb=0;
zc=z + (1.966/9.514);
}
printf("The fractional co-ordinates for Oxygen atoms
are:\n%f\t%f\t%f\n%f\t%f\t%f\n%f\t%f\t%f",xa,xb,xc,ya,yb,yc,za,zb,zc);
getch();
}
Now go back to accelrys Discovery studio and then goto Structure >> Crystal cell
>> create atom… a dialog box will appear. In it, click on the table button, the
periodic table will open up.Then choose Ti from it and click the “ok” button.
Now give the X, Y, Z fractional co ordinates (Wyckoff positions) of the Ti atoms
as calculated above.
Note: Care should be taken that no two co ordinates are same, i.e., avoid duplicity. Also
delete the Ti atoms lying outside the unit cell.
Figure 4.2 Duplicacy of Co ordinates
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Repeat the above step for oxygen atoms, the co ordinates of which are obtained
from the self designed program.(avoid duplicacy of co ordinates here too.)
Now select a Ti atom and then select adjacent O atom while pressing the
“SHIFT” key, so that both Ti and O are selected. Then go to Chemistry >> Bond
>> Single. A bond will be created between the two atoms now proceed further
keeping the picture of anatase unit cell in mind, obtained from literature.
Thus finally a unit cell of anatase is formed.
Figure 4.3 unit cell of anatase
Now to create a surface we have to extend this unit cell in the desired directions
(axis). Lets make a [1,0,1] surface comprising of 5 unit cells in X direction and 2
unit cells in the Z direction, this will give us a surface of dimensions 18.925 ×
3.785 × 19.028 Å3.
To implement this go to Structure >> Crystal cell >> Edit Parameters… the
Crystal Builder dialog box will open up. In it choose the Preference tab. In this,
select Symmetry Style as Positions from the drop down menu, set Special
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position tolerance to 0.05, uncheck the Proximity Binding check box, in view
range set A : 5 , B : 1 , C : 2. Then click on the “apply” button and then the “ok”
button. The surface gets generated!!
Figure 4.4 3D structure of Anatase Figure 4.5 3D structure of Anatase
Now save this as “.sd” file. Goto File >> Save As , write “Ligand.sd”, select a
preferred location to save the file and then click Save button.
Next step is to convert this file format to “*.pdb” format, for this go to Start menu
>> All Programs >> Open Babel 2.2.3 >> OpenBabelGUI. The program will open
up. In this select the input file format as “.sd”, then click browse, open the
location of the input file “Ligand.sd” and open it. Then choose the output format
as “.pdb”. Now enter the address of the output file, i.e., where it has to be saved,
give the file name as “Ligand.pdb”. Finally press convert button.
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Figure 4.6 OpenBabel
Open the “model.pdb” in Accelrys Discovery Studio. Goto Chemistry >>
Hydrogens >> Add, and then click save. Now our Protein is also ready.
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Figure 4.7 Visualization of 3D enzymes structure
Docking studies using PatchDock Server
Now we’ll goto PatchDock server(http://bioinfo3d.cs.tau.ac.il/PatchDock/ ).
Figure 4.8 Home Page of PatchDock
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In the receptor molecule option click “choose file” button,and select the protein
file “model.pdb”, from the location where it has been saved. Then in the Ligand
molecule option “choose file”, and select the ligand file “Ligand.pdb” ,from the
location where it has been saved.
Give your e-mail address in the space provided where the results would be sent.
Keeps the default clustering RMSD value, i.e., 4.0.
Select complex type from the drop down menu as Protein-Small Ligand.
Press “submit form” button. Results would be sent to the provided e-mail
address after sometime.
4.3 Results and Discussion
We have performed molecular docking method using Patchdock server to find out the
interaction between NNK Vs Nanoparticles and NNK Vs proteins involved in DNA
repair Pathways. The implemented hypothesis suggest that if NNK/NNAL and
nanoparticles would be present in the cellular system than nanoparticles could interact
with carcinogens like NNK and NNAL firstly on the basis of obtained binding energy
using PatchDock tool.
The Pathdock algorithm divides the molecular surface into shape-based patches. This
division addresses both the efficiency and at the same time, distinguishes between
residue types (polar/non-polar) in the patches. Further, we make use of residue hot
spots in the patches. Second, the method utilizes distance transform to improve the
shape complementarily function. Third, it implements faster scoring, based on multi-
resolution surface data structure. Our improved shape complementarily function
further contributes to the quality of the results. While here the docking is rigid, the
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utilization of the last three components enables us to permit more liberal intermolecular
penetration. Patchdock results showed nanoparticles could be able to trap cigarette
smoke carcinogens efficiently in the cellular system. The highest obtained binding
efficiency between NNK vs SWcNT is 2632 score in contrast with NNK Vs 3K05 shows
2454 score,which means NNK could interact with SWcNT more efficiently than 3K05.
Other part of the study shows that the highest binding efficiency NNAL vs SWcNT
=2746 score and NNAL vs TiO2 Rutile= 2110 score in contract with NNAL vs 2RBA
shows 1696 score. It is also signify that NNAL interact with SWcNT and TiO2 rutile
more efficiently than 2RBA.
Table 4.1 Comparison of Patch dock scores obtain from docked NNK vs Proteins and
NNK Vs Nanoparticles conformations
S.No. Protein’s
Name
Protein Vs
NNK
SWNT Vs
NNK
TiO2
Anatase Vs
NNK
TiO2
Rutile Vs
NNK
Fullerene
Vs
NNK
1. 1CKJ 2790 2632 2068 1360 910
2. 2O8B 2720 2632 2068 1360 910
3. 3K05 2454 2632 2068 1360 910
4. 3GQC 3054 2632 2068 1360 910
Table 4.2 Comparison of Patch dock scores obtain from docked NNAL Vs Proteins
and NNAL Vs Nanoparticles conformations
S.No. Protein’s
Name
Protein Vs
NNAL
SWNT Vs
NNAL
TiO2
Anatase
TiO2
Rutile
Fullerene
1. 1CKJ 3688 2746 2110 1360 954
2. 1Q2Z 3374 2746 2110 1360 954
3. 1T38 3240 2746 2110 1360 954
4. 2RBA 1696 2746 2110 1360 954
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Figure: 4.9 TiO2 Docked with 1CKJ Figure: 4.10 TiO2 docked with 1Q2Z
Figure 4.11 TiO2 Docked with 2O8B Figure 4.12 TiO2 docked with 1T38
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Figure 4.13 TiO2 Docked with 3GQC Figure 4.14 TiO2 Docked with 3K05
Figure 4.15 TiO2 Docked with 2RBA
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Figure 4.16 Fullerene docked with 1CKJ Figure: 4.17 Fullerene Docked with 1Q2Z
Figure 4.18 Fullerene Docked with 1T38 Figure 4.19 Fullerene Docked with 2O8B
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Figure: 4.20 Fullerene Docked with 3GQC Figure: 4.21 Fullerene Docked with 3K05
Figure: 4.22 Fullerene Docked with 2RBA
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Figure: 4.23 SWNT docked with 1CKJ Figure: 4.24 SWNT Docked with 1Q2Z
Figure:4.25 SWNT Docked with 1T38 Figure: 4.26 SWNT Docked with 2O8B
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Figure: 4.27 SWNT Docked with 3GQC Figure: 4.28 SWNT Docked with 3K05
Figure: 4.29 SWNT Doked with 2RBA
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Figure 4.30 visualization of SWcNT and NNAL interaction
Figure 4.31 visualization of SWcNT and NNK interaction
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4.4 Conclusion
As mentioned earlier, the fact that technical TiO2 is very often of the (metastable)
anatase form; most TiO2 nanomaterials are of anatase form, and in many cases anatase
is photocatalytically more active than rutile. This has motivated theoretical
investigations of anatase, but there are hardly any experiments on well-characterized
surfaces that would enable verification of these theoretical predictions. This lack of
experimental data is mostly due to the limited availability of anatase crystals of
sufficiently large size.
This study of anatase [1,0,1] surface may prove to be very valuable for biotechnologists
as this aspect of biotechnology has yet not been explored. The [1,0,1] surface is also the
surface mostly available for interactions, this surface is also found over TiO2 nanotubes,
which are presently the subject of interest of the research community of electronics and
nanotechnology innovators.In low and definite conc., TiO2 significantly reduced the
harmful compounds from the cigarette smoke (Qixin Deng et.al, 2011).
The scavenging capacities of the nanoparticles for PAH and other toxicants could
probably be attributed to their higher affinity towards the xenobiotics. The structural
properties and surface chemistry of nanoparticles are the players, further, extremely
high surface area to volume ratio results in multiple enhancements of such properties.
Our study is conformity of study of Qixin Deng et al.,2011, who reported the use of
titanate nanosheets and nanotubes are significantly reduces the harmful compounds in
tobacco smoke .Our study confirmed this action in Biological system that by using of
Bioinformatics tools we have done the comparative docking study between
Nanoparticles-biomolecules and NNK/NNAL-Nanoparticles, we concluded that
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SWcNT,TiO2-Biomolecules binding shown lower scores and NNK/NNAL-
Nanoparticles binding shown higher scores. Hence, Results clearly signifying that
SWcNT/TiO2 are binding with NNK/NNAL more efficiently than biomolecules.
4.4.1 Future Scope:
There is a lot to be done in this research work. We are just at the beginning; much have
yet to be studied. Further studies can be done by applying force fields like crystal-
CHARMm, CFF or SIBFA (these are the few force fields which deals with metals and
crystal structures) and then going for various interaction studies and energy
calculations. The major Hurdle in this work is that most of the softwares currently
available do not recognize, i.e., they do not contain information regarding
crystallographic bonding (or arrangements) and metallic atoms, their physical, chemical
and quantum mechanical properties for molecular dynamic simulations of the same.
There is an urgent requirement for a complete software package which can be used to
design and manipulate inorganic or organic crystals as well as the biomolecules. In this
chapter itself we have written a code in the C language to calculate the co ordinates of
oxygen atom with respect to the titanium atoms. This can be considered as part of a
larger software program.
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4.5 References
1. 25th anniversary of the Buckyball celebrated by interactive Google Doodle,
Telegraph.co.uk 4 September 2010.
2. Arndt, M.; et al. (1999). "Wave-particle duality of C60".Nature 401 (6754):
6802. Bibcode 1999 Natur.401.680A.doi:10.1038/44348. PMID 18494170.
3. Atkinson, Nancy (2010-10-27). "Buckyballs Could Be Plentiful in the
Universe". Universe Today. Retrieved 2010-10-28.
4. Baati, Tarek; Bourasset F, Gharbi N, Njim L, Abderrabba M, Kerkeni A, Szwarc
H, Moussa F (June 2012). "The prolongation of the lifespan of rats by repeated
oral administration of [60 fullerene"]. Biomaterials 33 (19): 4936
4946. doi:10.1016/j.biomaterials.2012.03.036.PMID 22498298.
5. Beavers, C.M.; et al. (2006). "Tb3N@C84: An improbable, egg-shaped
endohedral fullerene that violates the isolated pentagon rule". Journal of the
AmericanChemical Society128 (35):11352–3. doi:10.1021/ja063636k.PMID 16939248.
6. Beck, Mihály T.; Mándi, Géza (1997). "Solubility of C60".Fullerenes, Nanotubes
and Carbon Nanostructures 5 (2): 291. doi:10.1080/15363839708011993.
7. Bezmel'nitsyn, V.N.; Eletskii, A.V.; Okun', M.V. (1998). "Fullerenes in
solutions". PhysicsUspekhi 41 (11):1091.Bibcode 1998PhyU...41.1091B.doi:10.107
0/PU1998v041n11ABEH000502.
8. Blank, V. (1998). "Ultrahard and superhard phases of fullerite C60: Comparison
with diamond on hardness and wear". Diamond and Related Materials 7 (2–5):
427.Bibcode 1998DRM.....7..427B. doi:10.1016/S0925-9635(97)00232-X.
9. Bochvar, D.A.; Galpern, E.G. (1973). Dokl. Acad. Nauk SSSR 209: 610.
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10. Brown, S.B. (2004). "The present and future role of photodynamic therapy in
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