Model Chemistry as Science and Art
One should not become an artist because he can, but because he must. It is only for those who would be miserable without it.
Irving
Stone
PDB
ID-1BL8 POTASSIUM
CHANNEL (KCSA) FROM STREPTOMYCES
LIVIDANS
Highly specific membrane-spanning macromolecular structures, "ion channels", serve to facilitate and control the passage of selected ions across the lipid barrier. Of particular interest was the determination of the structure of the KcsA K+ channel from Streptomyces lividans. Because of its structural similarity to eukaryotic K+ channels, investigations of KcsA are expected to help improve the understanding of a large class of biologically important channels (B. Roux et al., 2000, Biochemistry, 39, pp. 13295-13306). The KcsA structure at 3.2 Å resolution allows direct observation of K+ ions in and near the selectivity filter as well as a water molecule coordinated with these K+ ions (D.A. Doyle et al., 1998, Science, 280, p. 69).
Highly specific membrane-spanning macromolecular structures, "ion channels", serve to facilitate and control the passage of selected ions across the lipid barrier. Of particular interest was the determination of the structure of the KcsA K+ channel from Streptomyces lividans. Because of its structural similarity to eukaryotic K+ channels, investigations of KcsA are expected to help improve the understanding of a large class of biologically important channels (B. Roux et al., 2000, Biochemistry, 39, pp. 13295-13306). The KcsA structure at 3.2 Å resolution allows direct observation of K+ ions in and near the selectivity filter as well as a water molecule coordinated with these K+ ions (D.A. Doyle et al., 1998, Science, 280, p. 69).
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PDB
ID-3M4E CRYSTAL
STRUCTURE OF THE M113N MUTANT OF
ALPHA-HEMOLYSIN BOUND TO
BETA-CYCLODEXTRIN
α-Hemolysin is a protein toxin secreted from Staphylococcus aureus, which forms a mushroom-shaped membrane-inserted heptamer. The channel-forming protein consists of seven chains, with 293 residues each. β-Cyclodextrin (βCD) belongs to the family of cyclodextrins, cyclic oligomers composed of α-D-glucose units, able to form host-guest complexes with a variety of organic molecules. It has been discovered that βCD is able to lodge in the interior of α-hemolysin (αHL) protein pore, resulting in altered conductance and charge selectivity of the channel. What is more interesting, βCD bound inside the channel protein preserved its ability to host-guest complexation, which revealed itself in additional current blockades. This made the αHL pore a stochastic sensor able to detect a single molecule of analyte by measuring ionic currents flowing through the channel (I.Y. Shilov and M.G. Kurnikova, 2003, J. Phys. Chem. B, 107, pp. 7189-7201).
α-Hemolysin is a protein toxin secreted from Staphylococcus aureus, which forms a mushroom-shaped membrane-inserted heptamer. The channel-forming protein consists of seven chains, with 293 residues each. β-Cyclodextrin (βCD) belongs to the family of cyclodextrins, cyclic oligomers composed of α-D-glucose units, able to form host-guest complexes with a variety of organic molecules. It has been discovered that βCD is able to lodge in the interior of α-hemolysin (αHL) protein pore, resulting in altered conductance and charge selectivity of the channel. What is more interesting, βCD bound inside the channel protein preserved its ability to host-guest complexation, which revealed itself in additional current blockades. This made the αHL pore a stochastic sensor able to detect a single molecule of analyte by measuring ionic currents flowing through the channel (I.Y. Shilov and M.G. Kurnikova, 2003, J. Phys. Chem. B, 107, pp. 7189-7201).
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PDB
ID-1Z0M THE
GLYCOGEN-BINDING DOMAIN OF THE
AMP-ACTIVATED PROTEIN KINASE
BETA1 SUBUNIT
AMP-activated protein kinase (AMPK) is a metabolic stress sensing protein kinase. AMPK activates fatty acid β oxidation, glycolysis, glucose transport, and stimulates food intake, while inhibiting fatty acid, triglyceride, and cholesterol synthesis. In this way, AMPK functions as a critical focal point for whole body and cellular mechanisms maintaining energy homeostasis. AMPK is αβγ heterotrimer; it requires the presence of all three subunits for activity. AMPK has been linked directly to glycogen metabolism by a number of observations. The molecular basis for relationship between AMPK and glycogen is now clearer with the recent identification of a glycogen binding domain (βGBD) in the β subunit. To understand the molecular mechanism of the interaction between AMPK and glycogen, the 3D atomic structure of AMPK βGBD in complex with the cyclic sugar β-cyclodextrin has been determined (G. Polekhina et. al., 2005, Structure, 13, pp.1453-1462).
AMP-activated protein kinase (AMPK) is a metabolic stress sensing protein kinase. AMPK activates fatty acid β oxidation, glycolysis, glucose transport, and stimulates food intake, while inhibiting fatty acid, triglyceride, and cholesterol synthesis. In this way, AMPK functions as a critical focal point for whole body and cellular mechanisms maintaining energy homeostasis. AMPK is αβγ heterotrimer; it requires the presence of all three subunits for activity. AMPK has been linked directly to glycogen metabolism by a number of observations. The molecular basis for relationship between AMPK and glycogen is now clearer with the recent identification of a glycogen binding domain (βGBD) in the β subunit. To understand the molecular mechanism of the interaction between AMPK and glycogen, the 3D atomic structure of AMPK βGBD in complex with the cyclic sugar β-cyclodextrin has been determined (G. Polekhina et. al., 2005, Structure, 13, pp.1453-1462).
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PDB
ID-1MF8 CRYSTAL
STRUCTURE OF HUMAN CALCINEURIN
COMPLEXED WITH CYCLOSPORIN A AND
HUMAN CYCLOPHILIN
Calcineurin (Cn), a Ca2+/calmodulin-dependent Ser/Thr protein phosphatase, is an important participant in signaling pathways that activate T cells. It is the target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. These drugs bind proteins known as cyclophilin (Cyp) and FK506-binding protein, respectively, and the drug-protein complexes in turn inhibit Cn. The crystal structure of a Cyp/CsA/Cn ternary complex has been determined to a resolution of 3.1 Å. The structure accounts for the effects of mutations in Cn on CsA-resistance and for the way modifications of CsA alter immunosuppressive activity (J. Jin and S.C. Harrison, 2002, PNAS, 99, 13522-13526).
Calcineurin (Cn), a Ca2+/calmodulin-dependent Ser/Thr protein phosphatase, is an important participant in signaling pathways that activate T cells. It is the target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. These drugs bind proteins known as cyclophilin (Cyp) and FK506-binding protein, respectively, and the drug-protein complexes in turn inhibit Cn. The crystal structure of a Cyp/CsA/Cn ternary complex has been determined to a resolution of 3.1 Å. The structure accounts for the effects of mutations in Cn on CsA-resistance and for the way modifications of CsA alter immunosuppressive activity (J. Jin and S.C. Harrison, 2002, PNAS, 99, 13522-13526).
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PDB
ID-3ERD HUMAN
ESTROGEN RECEPTOR ALPHA
LIGAND-BINDING DOMAIN IN COMPLEX
WITH DIETHYLSTILBESTROL AND A
GLUCOCORTICOID
The estrogen receptor a (ERα) regulates differentiation and maintenance of neural, skeletal, cardiovascular, and reproductive tissues. Compounds that modulate ERα transcriptional activity are currently being used to treat osteoporosis, cardiovascular disease, and breast cancer. Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. The crystal structure of the human estrogen receptor α (hERα) ligand-binding domain (LBD) to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator GRIP1 and the crystal structure of the hERα LBD bound to the selective antagonist 4-hydroxytamoxifen (OHT) has been determined. In the DES-LBD-peptide complex (ID-3ERD), the peptide binds as a short α helix to a hydrophobic groove the surface of LBD. In the OHT-LBD complex (ID-3ERT), helix 12 occludes the coactivator recognition groove by mimicking the interactions of the NR box peptide with the LBD (A.K. Shiau et al., 1998, Cell, 95, pp. 927-937).
The estrogen receptor a (ERα) regulates differentiation and maintenance of neural, skeletal, cardiovascular, and reproductive tissues. Compounds that modulate ERα transcriptional activity are currently being used to treat osteoporosis, cardiovascular disease, and breast cancer. Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. The crystal structure of the human estrogen receptor α (hERα) ligand-binding domain (LBD) to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator GRIP1 and the crystal structure of the hERα LBD bound to the selective antagonist 4-hydroxytamoxifen (OHT) has been determined. In the DES-LBD-peptide complex (ID-3ERD), the peptide binds as a short α helix to a hydrophobic groove the surface of LBD. In the OHT-LBD complex (ID-3ERT), helix 12 occludes the coactivator recognition groove by mimicking the interactions of the NR box peptide with the LBD (A.K. Shiau et al., 1998, Cell, 95, pp. 927-937).
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PDB
ID-1GWR HUMAN
OESTROGEN RECEPTOR ALPHA
LIGAND-BINDING DOMAIN IN COMPLEX
WITH 17BETA-OESTRADIOL AND TIF2
NRBOX3 PEPTIDE
The activation function 2/ligand-dependent interaction between nuclear receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit distinct preferences for such motifs depending both on the bound ligand and on the NR box sequence. To better understand the structural basis of motif recognition, the interaction between estrogen receptor α and the NR box regions of the p160 coactivator TIF2 has been characterized and the crystal structures of complexes between the ligand-binding domain of estrogen receptor α and 12-mer peptides from the Box 2 and Box 3 regions of TIF2 have been determined to a resolution of 2.4 Å. (A. Warnmark et al., 2002, J. Biol. Chem., 277, pp. 21862-21868)
The activation function 2/ligand-dependent interaction between nuclear receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit distinct preferences for such motifs depending both on the bound ligand and on the NR box sequence. To better understand the structural basis of motif recognition, the interaction between estrogen receptor α and the NR box regions of the p160 coactivator TIF2 has been characterized and the crystal structures of complexes between the ligand-binding domain of estrogen receptor α and 12-mer peptides from the Box 2 and Box 3 regions of TIF2 have been determined to a resolution of 2.4 Å. (A. Warnmark et al., 2002, J. Biol. Chem., 277, pp. 21862-21868)
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PDB
ID-1ERE HUMAN
ESTROGEN RECEPTOR LIGAND-BINDING
DOMAIN IN COMPLEX WITH
17BETA-ESTRADIOL
Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. The crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 Å have been reported (ID-1ERE and ID-1ERR, respectively). The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes (A.M. Brzozowski, 1997, Nature, 389, pp. 753-758).
Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. The crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 Å have been reported (ID-1ERE and ID-1ERR, respectively). The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes (A.M. Brzozowski, 1997, Nature, 389, pp. 753-758).
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PDB
ID-1ERR HUMAN
ESTROGEN RECEPTOR LIGAND-BINDING
DOMAIN IN COMPLEX WITH
RALOXIFENE
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PDB
ID-1AGU ADDUCTION OF
THE HUMAN N-RAS CODON 61
SEQUENCE WITH
BENZO[A]PYRENE-DIOL-EPOXIDE.
STRUCTURAL REFINEMENT OF THE
INTERCALATED ADDUCT FROM 1H NMR
The
genotoxicity of polycyclic
aromatic hydrocarbons (PAH) is
linked to metabolic activation
into reactive electrophiles
which react with DNA. In the
case of benzo-[a]pyrene,
microsomal P450 enzymes
catalyze formation of
diastereomeric 7,8-dihydrodiol
9,10-epoxides: [(+)-DE2] and
[(-)-DE2]. Evidence that
(+)-DE2 had the greatest
binding affinity to DNA was
obtained from reactions using
diastereomeric mixtures of the
epoxides with DNA, followed by
degradation and analysis.
Identification of the DNA
adducts revealed that the
(+)-DE2 adduct formed between
the 2-amino group of guanine
and C10 of the PAH, is the
major product. Mutagenesis
results were consistent with
the hypothesis that the
diastereomeric diol epoxides
represented the ultimate
carcinogenic species. (I.S.
Zegar et al., 1996,
Biochemistry, 35,
pp. 6212-6224).
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PDB
IDs-3AB4, 6B2C INHIBITION OF MACROPHAGE MIGRATION INHIBITORY FACTOR
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is extensively expressed in many mammalian cell types including endothelial cells, macrophages, and T-cells. High MIF levels are associated with numerous inflammatory and neurological disorders; MIF also plays a role in cancer through regulation of cell proliferation and promotion of angiogenesis. Consequently, there has been significant activity in searching for inhibitors of MIF signaling. Discovery of MIF inhibitors has focused on small molecules that bind to and protrude from the tautomerase active sites causing interference with the receptor activation. (W.L. Jorgensen and co-authors:
2017, ACS Med. Chem. Lett., 8,
pp. 1287-1291 and 2018, J. Med. Chem., 61, pp. 8104-8119).
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PDB
ID-2HI4 CRYSTAL
STRUCTURE OF HUMAN MICROSOMAL
P450 1A2 IN COMPLEX WITH
ALPHA-NAPHTHOFLAVONE
Microsomal
cytochrome P450 family 1
enzymes play prominent roles
in xenobiotic detoxication and
procarcinogen activation. P450
1A2 is the principal
cytochrome P450 family 1
enzyme expressed in human
liver and participates
extensively in drug
oxidations. This enzyme is
also of great importance in
the bioactivation of mutagens,
including the N-hydroxylation
of arylamines. The structure
of human P450 1A2 in complex
with the inhibitor α-naphthoflavone
was determined to a resolution
of 1.95 Å. α-Naphthoflavone
is bound in the active site
above the distal surface of
the heme prosthetic group. The
structure reveals a compact,
closed active site cavity that
is highly adapted for the
positioning and oxidation of
relatively large, planar
substrates. This unique
topology is distinct from
known active site
architectures of P450 family 2
and 3 enzymes and demonstrates
how P450 family 1 enzymes have
evolved to catalyze
efficiently polycyclic
aromatic hydrocarbon (PAH)
oxidation. (S. Sansen et al.,
2007, J. Bio. Chem., 282,
pp. 14348-14355).
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POLYCYCLIC
AROMATIC HYDROCARBONS-FOREVER
YOUNG
The study of
polyarenes, or polycyclic
aromatic hydrocarbons (PAH),
spans several branches of
chemistry, and extends beyond
it: polyarenes challenge our
understanding of aromaticity
and participate in various
type of reactions; as
thermodynamic "sinkholes",
they are abundant in
interstellar matter and in
fire soot; and although
polyarenes threaten us by
their carcinogenicity, they
also serve as model compounds
and possible precursors for
novel carbon-rich materials
such as fullerenes, nanotubes,
and graphene. One of the most
intriguing features of
polyarenes is their ability to
serve as synthetic metals,
i.e., accept several electrons
by chemical reduction. In the
study of polyarene anions,
experiment and computation
have often gone hand in hand.
Experimentalists turn to
computations to characterize
these reactive intermediates
better, to explain
experimental results and to
offer insights and predictions
to shape future research.
Computational contributions
range from routine auxiliary
characterization of geometry,
energy, spectrum, and charge
distribution to studies in
which experiment and
computation are closely
intertwined, and on to purely
theoretical studies that
direct research into uncharted
lands.(D. Eisenberg and R.
Shenhar, 2012, WIREs Comput.
Mol. Sci., 2,
p. 525-547; R. Rieger and K.
Müllen, 2010, J. Phys. Org.
Chem., 23,
pp. 315-325).
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POLYCYCLIC
AROMATIC HYDROCARBONS AS
BUILDING BLOCKS OF NOVEL
SUPRAMOLECULAR COMPLEXES
In recent
years, major research efforts
have been devoted to the
investigation of the physical
and chemical properties of
nanoscale carbon materials
such as fullerenes, carbon
nanotubes and graphenes with
the intention of developing
devices that could lead future
technologies. Because of its
unique structure and
electronic properties,
graphene has drawn the
attention of scientists for
novel applications in
molecular electronics.
Polycyclic aromatic
hydrocarbons (PAH) constitute
a class of molecules whose
members are formed by
condensing benzenoid units.
The first member of this
particular series is benzene,
while graphene may be seen as
the ultimate member. In
between, there exist PAH
molecules having planar
disk-shaped structures such as
triphenylenes. Non-planarity
of the conjugated carbon
network associated with
incorporation of five-membered
rings (e.g., buckybowls,
fullerenes), cyclophane-type
bridges and bulky
substituents, introduced novel
structural motifs to the
chemistry of PAH and inspired
construction of large highly
non-planar molecular
structures capable of forming
functionalized host-guest
complexes of various sizes and
shapes. (T. Hasobe, 2012,
Phys.Chem.Chem. Phys., 14,
pp. 15975-15987; A. Sygula,
2011, Eur. J. Org. Chem., pp.
1611-1625).
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FUNCTIONAL SELF-ASSEMBLED MOLECULAR ARCHITECTURES
The construction of supramolecular architectures attracts a great deal of attention because of their unique morphologies and potential applications. Self-assembly as a method for organizing molecules allows to design size- and shape-controlled molecular architectures at the nano- and micro-scales. Such a technique makes it possible to achieve novel molecular properties in comparison with those of the corresponding monomeric forms. Spontaneous self-assembly of amphiphilic molecules is an efficient technique that employs biodegradable polymers, liposomes, and cyclodextrines (CDs) as building blocks to fabricate nanostructures with desired properties and performance. The driving force of self-assembly in supramolecular structures depends on intermolecular interactions such as van der Waals interactions, formation of hydrogen and coordination bonds, and π-π interactions. Cooperative and/or competitive effects between different types of interactions lead to the formation of a variety of functional moleculer complexes suitable for a broad range of practical applications. (T. Hasobe, 2012, Phys. Chem. Chem. Phys., 14, pp. 15975-15987; F.B. De Sousa et al., 2012, Phys. Chem. Chem. Phys., 14, pp. 1934-1944; J.C. Barnes et al., 2013, JACS, 135, pp.183-192).
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INTRIGUING NON-PLANAR CARBON MORPHOLOGIES
Curved forms of carbon-rich compounds have been known since the discovery of fullerenes and carbon nanotubes. More recently, other non-planar carbon morphologies occurring naturally and produced synthetically were introduced. large scale production of conical nano structures is possible through pyrolysis of hydrocarbons in plasma torch process. The resulting carbon cones and disk-shaped particles occur in several distinctly different forms. The structure and properties of these morphologies have been relatively little explored. It was found that carbon nano-cones exhibit several interesting structural features; they were characterized using transmission electron microscopy (TEM), synchrotron X-ray and electron diffraction. (S.N. Naess et al., 2009, Sci. Technol. Adv. Mater., 10, 065002.)
Single-wall carbon nanohorns are cylinders made of single graphene sheets with diameters of 2-5nm and length 40-50nm. They are of high purity (>90%, no metal) and holes are easily opened by heating (400-600°C) in an oxygen gas or air as evidenced directly by TEM and indirectly by the pore volume increase estimated from nitrogen adsorption. The size and number of holes can be controlled by adjusting the combustion conditions. The effect of holes on incorporation and release of materials were thoroughly investigated. It have been reported that the potential applications of such morphologies include catalyst support, gas storage media, molecular sieves, photoelectrical solar cells, and drug carriers. (R. Yuge et al., 2007, J. Phys. Chem. C, 111 pp. 7348-7351.)
Y shaped nanomaterials (Y rings and Y junctions) are made solely of carbon nanotubes. Y rings attracted attention of researchers due to the possibility of quantum interference phenomena. Y junctions were experimentally observed by TEM under electron beam irradiation. It was shown that the electrical transport of these Y shaped systems exhibit interesting rectification properties. This fact suggests the possibility of using Y junctions as nanoscopic three-point transistors. (D. Grimm et al., 2005, Physical Review B, 71, p. 155425.)
Single-wall carbon nanohorns are cylinders made of single graphene sheets with diameters of 2-5nm and length 40-50nm. They are of high purity (>90%, no metal) and holes are easily opened by heating (400-600°C) in an oxygen gas or air as evidenced directly by TEM and indirectly by the pore volume increase estimated from nitrogen adsorption. The size and number of holes can be controlled by adjusting the combustion conditions. The effect of holes on incorporation and release of materials were thoroughly investigated. It have been reported that the potential applications of such morphologies include catalyst support, gas storage media, molecular sieves, photoelectrical solar cells, and drug carriers. (R. Yuge et al., 2007, J. Phys. Chem. C, 111 pp. 7348-7351.)
Y shaped nanomaterials (Y rings and Y junctions) are made solely of carbon nanotubes. Y rings attracted attention of researchers due to the possibility of quantum interference phenomena. Y junctions were experimentally observed by TEM under electron beam irradiation. It was shown that the electrical transport of these Y shaped systems exhibit interesting rectification properties. This fact suggests the possibility of using Y junctions as nanoscopic three-point transistors. (D. Grimm et al., 2005, Physical Review B, 71, p. 155425.)
In MOLECULAR COMPOSITIONS below PDB files 1N7D, 1YPQ, 1Y58, and 3ERT (for snow storm) were used in conjunction with poly(β-amino ester)s, fully MM+ optimized carbon morphologies and a few intermediates of optimization process. Molecular systems were visualized by VMD and POV-Ray.
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MOLECULAR FANTASY-DINOSAURS OF 21-ST CENTURY
(1LX5, 1ERE, 1GWR PDB files combined and
3ERT PDB file duplicated)
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MOLECULAR FANTASY-BLACK SEA: IS IT WHAT WE WANT?
(1LX5, 1BKB, 3W9T, 1GWR PDB files combined with
selected models of CNTs. Conversion of VMD to POV-Ray visualization was tested.)
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(Click on the
thumbnail to see the selected images enlarged)
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THE IMAGES PUBLISHED HERE ARE SUBJECT TO COPYRIGHT. PLEASE DO NOT REPRODUCE WITHOUT PERMISSION OF THE AUTHOR.
THANK YOU!