In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4 Page -141- 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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In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4
Page -141-
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
In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4
Page -142-
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
In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4
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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
In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4
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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
In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4
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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.
In silico designing and synthesis of nanoparticles……………………..biomolecules Chapter 4
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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