Molecular Modeling Studies
on Binding of bFGF to Heparin and its Receptor FGFR1
King Lam, V.S.R. Rao and Pradman K. Qasba*
Structural Glycobiology Section, Laboratory of Experimental and Computational
Biology, National Cancer Institute, NCI-FCRDC,
Frederick, Maryland 21702
*Author to whom correspondence should be addressed. Phone: 301-846-1933;
Fax: 301-846-7149; E-mail: qasba@helix.nih.gov
Abstract
Sugar induced protein-protein interactions play an important role in several biological processes. The carbohydrate moieties of proteoglycans, the glycosaminoglycans, bind to growth factors with a high degree of specificity and induce interactions with growth factor receptors, thereby regulate the growth factor activity. We have used molecular modeling method to study the modes of binding of heparin or heparan sulfate proteoglycans (HSPGs) to bFGF that leads to the dimerization of FGF receptor 1 (FGFR1) and activation of receptor tyrosine kinase. Homology model of FGFR1 Ig D(II)-D(III) domains was built to investigate the interactions between heparin, bFGF and FGFR1. The structural requirements to bridge the two monomeric bFGF molecules by heparin or HSPGs and to simulate the dimerization and activation of FGFR1 have been examined. A structural model of the biologically functional dimeric bFGF-heparin complex is proposed based on: (a) the stability of dimeric complex, (b) the favorable binding energies between heparin and bFGF molecules, and (c) its accessibility to FGFR1. The modeled complex between heparin, bFGF and FGFR1 has a stoichiometry of 1 heparin: 2 bFGF: 2 FGFR1. The structural properties of the proposed model of bFGF/heparin/FGFR1 complex are consistent with the binding mechanism of FGF to its receptor, the receptor dimerization, and the reported site-specific mutagenesis and biochemical cross-linking data. In the proposed model heparin bridges the two bFGF monomers in a specific orientation and the resulting complex induces FGF receptor dimerization, suggesting that in the oligosaccharide induced recognition process sugars orient the molecules in a way that brings about specific protein-protein or protein-carbohydrate interactions.
The Role of Bound Water
in the Stability of the Triple-Helical Conformation of (Pro-Pro-Gly)10
Craig A. Gough1*, Russell W. Anderson2 and Rajendra S. Bhatnagar1,2*
1Box 0424,
University of California, San Francisco
San Francisco, CA 94143-0424
2University of California San Francisco and
Berkeley Graduate Group in Bioengineering
Present Address:
HNC Software
5930 Cornerstone Court West,
San Diego, CA 92121-3728
*Authors to whom correspondence should be addrtessed.
C.A. Gough: E-mail: gough@collagen.ucsf.edu
R.S. Bhatnagar: Phone: 415-476-2923; Fax: 415-476-4204; E-mail: bhatnag@collagen.ucsf.edu
Abstract
There is significant experimental evidence for bound water in collagen
and related polymers. (Pro-Pro-Gly)10, {(PPG)10} is a polymer that forms a collagen-like triple-helical
structure in aqueous solution. Like collagen, (PPG)10
adopts a structure in which side chains are mostly exposed to solvent, and
the backbone polar groups are limited in their ability to form hydrogen
bonds with each other. (PPG)10, like collagen, also
has many of its backbone polar groups in positions that inhibit complete
solvation in aqueous solution; thus the necessity of bound waters for stabilization
of the structure. We have constructed a model for bound waters in (PPG)10, based on an examination of the geometry and steric environment
of the backbone polar groups. As will become clear, the number of bound
waters is determined by the geometry of the backbone carbonyl groups and
the steric crowding surrounding them. In this model, each water forms one
hydrogen bond with each of two backbone carbonyls from a glycine and a proline
in different monomer chains, thus bridging the two carbonyls. The carbonyls
in question are quite sterically crowded by neighboring (PPG)10
atoms and would not be likely to experience complete solvation by
bulk solvent in aqueous solution. The bound waters are therefore likely
to be present even in solution, since otherwise the unsatisfied hydrogen-bonding
potential of the carbonyls would destabilize the structure. Other carbonyls
also are sterically crowded and possibly prevented from experiencing full
solvation, but are not in a favorable geometry for such bridging hydrogen
bonds. The intra- and inter-chain interactions found in a previous computational
study of (PPG)10 without bound waters are not disrupted
by the addition of waters.
Microperoxidase-11: Molecular
Dynamics and Q-Band Excited Resonance Raman of the Oxidized, Reduced and
Carbonyl Forms
Monique Laberge*1, Andrew J. Vreugdenhil2, J. M. Vanderkooi1 and
Ian S. Butler2
1Johnson Research Foundation, Department of Biochemistry &
Biophysics, University of Pennsylvania,
Philadelphia, PA 19104
2Department of Chemistry, McGill University,
Montreal, QC, Canada
*Author to whom correspondence should be addressed. Phone: 215-898-8783;
Fax: 215-573-2042; E-mail: labergem@mail.med.upenn.edu
Abstract
Resonance Raman spectra with Q-band excitation are reported for microperoxidase-11,
the cytochrome c analog. Spectra were acquired in the mid-frequency range
for the oxidized, and reduced forms of the undecapeptide, as well as for
the imidazole and carbonyl complexes. Oxidation and spin state marker bands
of the undecapeptides are consistent with a six-coordinate, low spin iron
in both oxidation states. Porphyrin core size correlations yield a porphyrin-centre
to pyrrole-nitrogen distance of 2.00 Å for MP11, suggestive of a six-coordinate
species in a distorted heme environment. Molecular dynamics results show
that the non-planarity of the heme of the parent cytochrome is conserved
in the microperoxidase and its carbonmonoxy analog.
A Proteinase K Inhibitor
Using alpha,beta-Unsaturated (Dehydro) Residues: A Presumptive Model
Gita Subba Rao*, Sneh Arora and Sarika Kataria
Department of Biophysics, All India Institute of Medical Sciences, New Delhi-110029,
India
*Author to whom correspondence should be addressed. Phone: 91-11-6864851;
Fax: 91-11-6862663; E-mail: gitarao@medinst.ernet.in
Abstract
Enzymes of the subtilisin family, of which proteinase K is a member,
have been studied extensively on account of their numerous biological applications.
Specific inhibitors of the proteinases are of immense importance in regulating
their activity so as to protect the cells against uncontrolled proteolysis.
Using the specific design principles of peptides containing dehydro-Alanine
(DeltaAla), generated by our theoretical calculations, we present here the
design of an inhibitor of proteinase K. Energy minimization and molecular
modeling of the interaction of the designed tetrapeptide with the recognition
site of proteinase K indicate that it is an effective inhibitor.
Different Types of Interactions
Involving Cysteine Sulfhydryl Group in Proteins
Debnath Pal and Pinak Chakrabarti*
Department of Biochemistry, Bose Institute, P-1/12, CIT Scheme VIIM, Calcutta
700 054, India
*Author to whom correspondence should be addressed. Fax: 091-33-334-3886;
E-mail: pinak@boseinst.ernet.in
Abstract
Various types of interactions involving the sulfhydryl group of free
cysteine residues have been analyzed using known protein structures. In
a hydrogen bond the -SH group is more amenable to donating its proton to
a carbonyl group, rather than acting as a proton acceptor. It rarely interacts
with a carboxylate group, and is a poor ligand to bind an anionic substrate.
It is quite prone to make contacts that are definitely non-hydrogen bond
type. In the S···C=O interaction the S atom is placed
on the face of an amide group (mostly from the main-chain, but there are
cases from the side-chain also) close to the C atom. Cases of S···N
interaction, where the S atom is on top of the N atom of another residue
(both main-, as well as side-chains, including the guanidinium group) are
also observed. A considerable number of Cys residues have aromatic residues
as neighbors, and here too, the preferred mode of interaction is along the
face. The intra-residue S···C=O interaction constrains
the main-chain and side-chain torsion angles (y and c1),
whereas the inter-residue interactions are non-local and stabilize the tertiary
structure. The S···C=O interaction may have a role
in lowering the pKa values of the Cys residues
in enzyme active sites.
Quantum Molecular Modeling
of the Elastinic Tetrapeptide Val-Pro-Gly-Gly
H. Broch1, M. Moulabbi1,
D. Vasilescu1* and A.M. Tamburro2
1Laboratory of Biophysics GRECFO, University of Nice-Sophia
Antipolis, Parc Valrose, 06108 Nice, Cedex 2, France
2Department of Chemistry, Università
della Basilicata, Potenza, Italy
*Author to whom correspondence should be addressed. Phone:33 4 92 07 63
10; Fax: 33 4 92 07 63 10; E-mail: vasilesc@unice.fr
Abstract
The free Val-Pro-Gly-Gly tetrapeptide belonging to the Proline-rich sequences
of elastin has been studied both theoretically and experimentally.The molecular
modelisation was carried out using AM1 and ab initio quantum computations
while the conformation in solution was ascertained by circular dichroism
spectroscopy performed on the synthesized tetrapeptide. Experimental and
theoretical investigations lead to the conclusion that the most probable
structure is constituted by a type II beta-turn.
Xray Studies on Crystalline Complexes Involving Amino Acids and Peptides XXXIV. Novel Mode of Aggregation, Interaction Patterns and Chiral Effects in the Maleic Acid Complexes of DL- and L- Arginine.
R. Ravishankar, Nagasuma R. Chandra and M. Vijayan*
Molecular Biophysics Unit, Indian Institute of Science, Bangalore - 560
012, India
*Author to whom correspondence should be addressed Phone: 091-80-334-6765;
Fax: 091-80-334-1683, 091-80-334-8535; E-mail: mv@mbu.iisc.ernet.in
Abstract
Amino acid - carboxylic acid complexes provide useful information in relation to molecular interactions in present day biological systems and to prebiotic self-organisation. The crystal structures of the complexes of maleic acid with DL- arginine (orthorhombic; Pca21; a=15.9829, b=5.4127, c=16.1885; R=0.0522 for 956 reflections) and L- arginine (triclinic; P1; a=5.2641, b=8.0388, c=9.7860, alpha=106.197, beta=97.275, g=101.64; R=0.039 for 1749 reflections) have been determined. The complexes are made up of positively charged zwitterionic arginine molecules and negatively charged semi-maleate ions which contain an intramolecular symmetric O--H--O hydrogen bond. In both the structures, the amino acid molecules aggregate into layers. In each layer, S2 head-to-tail sequences are interconnected through specific intermolecular interactions between a-carboxylate and guanidyl groups, an arrangement observed for the first time in crystal structures involving arginine. The carboxylate-guanidyl interactions are of different types in the two complexes and consequently aggregation patterns in them exhibit substantial differences. Interactions between the amino acid layers involve the semi-maleate ions in both the complexes. In addition, water-bridges also exist in the L complex. The full potential of the guanidyl group for specific interactions is realized in both the structures. The L complex contains an array of water-mediated salt bridges. The structures demonstrate that the effect of chirality on molecular aggregation can span a wide range.
Spatial Structure Model of
the CD4 Receptor-Binding Site of the HIV Envelope Protein gp120
Alexander M. Andrianov*
Institute of Bioorganic Chemistry, Belarus Academy of Sciences, Zhodinskaya
St., 5/2, 220141 Minsk, Republic of Belarus
*For author correspondence: Phone: 0-375-17-2647271; Fax: 0-375-17-2637132;
E-mail: ibochbel@eco2.iasnet.com
Abstract
In this study we have undertaken attempt to predict 3D structure of the
CD4 receptor-binding site of the HIV envelope protein gp120. The structure
of this site has been constructed by the analysis of low-energy conformers
of peptide T, an HIV reproduction inhibitor with amino acid sequence corresponding
to the fragment Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr of protein gp120, ensuring
the interaction of virus with T4 lymphocytes. To do this, the following
researches have been carried out: i) the spatial structure models of peptide
T and similar fragment 4-11 of an analogues of vasoactive intestinal peptide
have been modeled by the restrained molecular mechanics method developed
earlier, ii) conformational parameters of these models have been compared
to geometrical characteristics of homologous segments of unrelated proteins
with known spatial structures. The following major conclusions have been
made based on the comparative analysis: i) the conformation of C-terminal
fragment Thr-Thr-Asn-Tyr-Thr of peptide T, responsible for the biological
activity of the molecule, does not undergo the essential distortions while
embedding into the peptide chains of unrelated proteins; ii) this conformation,
that is realized in isolated molecule and includes two consecutive reverse
turns of the polypeptide chain, adequately describes the main conformational
features of an appropriate site of the HIV protein gp120; iii) the fragment
Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr of protein gp120 accepts one of six spatial
forms which are characteristic for peptide T.
RNA-Ascorbate Interaction
M.C. Djoman, J. F. Neault, S. Hashemi-Fesharaky and H. A. Tajmir-Riahi*
Department of Chemistry-Biology, University of Québec at Trois-Rivières,
C.P. 500, Trois-Rivières (Québec) Canada G9A 5H7
*Author to whom correspondence should be addressed. Phone: 819-375-5052;
Fax: 819-376-5084; E-mail: Tajmirri@uqtr.uquebec.ca
Abstract
Ascorbic acid and divalent iron salts have been widely used to investigate the effects of reactive oxygen species in different biological targets such as nucleic acids, proteins and lipids. This study was designed to examine the interaction of yeast RNA with vitamin C in aqueous solution at physiological pH with drug/RNA(P)(P=phosphate) molar ratios of r=1/80, 1/40, 1/20, 1/10, 1/4 and 1/2. Absorption spectra and Fourier transform infrared (FTIR) difference spectroscopy were used to determine the ascorbate binding mode, binding constant, sequence selectivity and RNA secondary structure in aqueous solution.
Spectroscopic evidence showed that at low drug concentration (r=1/80 and 1/40), no major ascorbate-RNA interaction occurs, while at higher drug concentrations (r>1/40), a major drug-RNA complexation was observed through both G-C and A-U base pairs and the backbone phosphate groups with k=31.80 M-1. Evidence for this comes from large perturbations of the G-C vibrations at 1698 and 1488 cm-1 and the A-U bands at 1654 and 1608 cm-1 as well as the phosphate antisymmetric stretch at 1244 cm-1. At r>1/10, minor structural changes occur for the ribose-phosphate backbone geometry with RNA remaining in the A-family structure. The drug distributions around double helix were about 55% with G-C, 33% A-U and 12% with PO2 groups. A comparison between ascorbate-RNA and ascorbate-DNA complexes showed minor differences. The ascorbate binding (H-bonding) is via anion CO and OH groups.
An RNA Model System for Investigation
of Pseudouridine Stabilization of the Codon-Anticodon Interaction in tRNALys, tRNAHis and tRNATyr
Darrell R. Davis*, Charles A. Veltri and Leeanne Nielsen
Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah
84112-5820
*Author to whom correspondence should be addressed. Phone: 801 581-7006;
Fax: 801 581-7087; E-mail: davis@adenosine.pharm.utah.edu
Abstract
The nucleoside conformation of pseudouridine (y) was investigated in
a series of RNA oligonucleotides and compared with the same sequences containing
the parent, unmodified uridine nucleoside. 1H NMR spectroscopy
was used to determine the glycosyl conformational preference in pseudouridine
systems at the nucleoside level; these experiments were extended to trimers,
and ultimately to RNA tetraloop hairpins that are models for the codon-anticodon
interaction in tRNA. ROESY 1D and 2D NMR experiments were used to measure
the nucleoside conformational preference as a function of temperature. The
thermodynamic stability of the RNA tetraloops was also analyzed using UV
monitored Tm experiments which established that pseudouridine
has a very strong stabilizing effect on double-stranded, base pairing interactions
when the modification is located within a base-paired region. This was shown
for a tetraloop hairpin model of the codon-anticodon interaction in tRNATyr which contains a y at position 35. Pseudouridine also
stabilizes double-stranded RNA when the y modification is in a single-stranded
region adjacent to a duplex region as occurs for y at positions 38 or 39
in tRNALys and tRNAHis. These
results establish that pseudouridine modification of RNA is a powerful and
versatile mechanism for stabilizing local RNA structure in both single-stranded
and double-stranded regions. Previously postulated roles for pseudouridine
as a "conformational switch" are unlikely in light of the increased
barrier to rotation about the glycosyl bond upon modification of uridine
to pseudouridine. The Tm and NMR data show that local
RNA stacking stabilization as a result of y will stabilize adjacent double-stranded
RNA regions such as the codon-anticodon interaction in tRNA.
Spectroscopic Investigation of an Intramolecular DNA Triplex Containing both G.G:C and T.A:T Triads and Its Complex with Netropsin
Claire Gondeau, Jean-Claude Maurizot and Maurice Durand*
Centre de Biophysique Moléculaire, UPR n° 4301 de CNRS Conventionée
avec l' Université d'Orleans.Rue Charles Sadron, 45071 Orléans
Cedex 2, France
*Author to whom correspondence should be addressed. Phone: (33) 02 38 25
78 58: Fax: (33) 02 38 63 15 17; E-mail: durand@cnrs-orleans.fr
Abstract
The triple helix formation by the oligonucleotide 5'd(G4T4G4-[T4]-G4A4G4-[T4]-C4T4C4) ([T4] represents
a stretch of 4 thymine residues) has been investigated by UV absorption
spectroscopy and circular dichroism. In a 10 mM sodium cacodylate, 0.2 mM
disodium EDTA (pH 7) buffer, we show the following significant results:
i) In the absence of MgCl2, the oligonucleotide adopts
a hairpin duplex structure with the dangling tail 5'd(G4T4G4-[T4]). This 5' extremity, which contains separated runs of
four guanine residues, does not assume the expected tetraplex conformation
observed when this sequence is free. ii) In the presence of MgCl2,
the oligonucleotide folds back on itself twice to give a triple helix via
a double hairpin formation, with [T4] single-strand
loops. iii) The addition of high concentration of KCl to the preformed triplex
does not disrupt the structure. Nevertheless, if the oligonucleotide is
allowed to fold back in the presence of K+, triplex
formation is inhibited. Circular dichroism studies demonstrate that the
oligonucleotide adopts a dimeric conformation, resulting from the association
of two hairpin duplexes, via the formation of an antiparallel G-quadruplex
by the telomeric 5'd(G4T4G4-[T4]) extremities.
iv) Under the experimental conditions used in this report, the triplex melts
in a monophasic manner. v) Netropsin, a DNA minor groove ligand, binds to
the central site A4/T4 of the
duplex and to that of the triplex in an equimolar stoichiometry. In contrast
with previous studies concerning pyr.pur:pyr triplexes, thermal denaturation
experiments demonstrate that the netropsin binding stabilizes the intramolecular
triplex.
Sequence Specific Interaction
of the Antiretrovirally Active Drug Hypericin with 5'ATGGCAGGATAT3' Oligonucleotide:A
Resonance Raman Spectroscopy Study
E. Kocisova1, L. Chinsky2
and P. Miskovsky1*
1Department of Biophysics, P. J. Safarik UniversityJesenna
5, 04154 Kosice, Slovak Republic
2L.P.B.C. (CNRS URA 2056), Université
P. et M. Curie,Place Jussieu - case 138, 75252 Paris Cedex 05, France
*Author to whom correspondence should be addressed.Phone: + 421 95 62 229
86; Fax: + 421 95 62 221 24, E-mail: misko@kosice.upjs.sk
Abstract
The resonance Raman spectra of two oligonucleotides and their complexes
with potent antiretrovirally and antineoplastic active photochemical drug
hypericin are reported. The Raman spectra of two oligonucleotides containing
twelve base pairs on addition of hypericin (one and two molecules per one
oligonucleotide) were compared. The first one contains the first nine base
pairs of the "rev" gene coming from HIV genome with three base
pairs added to stabilize the duplex (5'ATGGCAGGATAT3') and the second one
consists of the same content of the nucleotide bases but in changed sequence
order which serves as a control sequence (5'ACGTGATGATGA3'). Differences
in the spectra of the "rev" gene sequence and control sequence
in interaction with the drug indicate that: i) the AG and GA nucleotide
doublets are structurally specific targets for hypericin and ii) the hypericin
interaction with 5'AG3' target is stronger than with 5'GA3' one.
Molecular Dynamics Simulation of a 13-mer Duplex DNA: A PvuII Substrate
A.S. Kolaskar1* and R.R. Joshi2
1Bioinformatics Centre, University of Pune, Ganeshkhind, Pune-411007,
India
2Centre for Development of Advanced Computing,
University of Pune Campus, Pune-411007, India
*Author to whom correspondence should be addressed. Phone: +91 212 350195,
+91 212 355039; Fax: +91 212 350087; E-mail: kolaskar@bioinfo.ernet.in
Abstract
Parallel version of AMBER 4.1 was ported and optimised on the Indian
parallel supercomputer PARAM OpenFrame built around Sun Ultra Sparc processors.
This version of AMBER program was then used to carry out molecular dynamics
(MD) simulations on 5'-TGACCAGCTGGTC-3', a substrate for PvuII enzyme. MD
simulations in water are carried out under following conditions: (i) unconstrained
at 300 K (230 ps); (ii) unconstrained at 283 K (500 ps); (iii) Watson-Crick
basepair constrained at 283 K (1 ns); and (iv) Watson-Crick basepair constrained
with ions at 283 K (1.2 ns). In all these simulation studies, the molecule
was observed to be bending and maximum distortions in the double helix around
was seen around the G7:C7' basepair, which is the phosphodiester bond that
is cleaved by PvuII. Analysis of MD simulation with ions carried out for
1.2 ns also pointed out that the conformation of double helix alternates
between a conformation close to B-form and close to A-form. It is argued
that a bent non-standard conformation is recognised by the PvuII enzyme.
The maximum bend occurs at the G7:C7' region, weakening the phosphodiester
bond and allows His48 to get placed in such a fashion to permit the scission
through a general base mechanism. The bending and distortion observed is
a property of the sequence which acts as a substrate for PvuII enzyme. This
is confirmed by carrying out MD studies on the Dickerson's sequence d(CGCGAATTCGCG)2 as a reference molecule, which practically does not bend
or get deformed.
Small Circles of Helical
DNA Obtained on the Basis of Transcriptional Pause Sites Sequence
V.B. Fedoseyeva* and A.A. Alexandrov
Institute of Molecular Genetics, Russian Academy of Sciences Kurchatov Sq.,
Moscow, Russia 123182
*Author to whom correspondence should be addressed. Phone:7095-196-02-01;
Fax: 7095-196-02-21; E.mail:img@glasnet.ru
Abstract
The 21-base pair synthetic DNA duplexes with basic 'pause-motif' site
('CATGC') were ligated head-to-tail to produce linear and circular multimers.
This also was done from other closely related sequences. Electrophoretic
mobilities of the linear multimers in polyacrylamide gels were determined
under the standard and modified conditions. We revealed that small linear
multimers ( ~ 90 bp ) were characterized by comparable value of gel retardation
relative to the well known curved DNA, while longer multimers (130~170 bp)
had only slightly expressed mobility anomaly. Nevertheless these multimers
containing nontruncated 'pause-motif' were capable of cyclization, in particular,
formation of unusually small circles while truncated ones were not. We conclude
that basic 'pause-motif' site increases the closure ability while the multimers
based on truncated 'pause motif' fail to curve into the small circles. We
tend to explain this situation as a result of intrinsic bending as well
as the influence of the thermal fluctuations of DNA, the latter most probably
can be associated with 'pause motif'. We have estimated the equilibrial
and maximal bend angles per 10.5 bp to be 12°~16° and 32° accordingly
under experimental conditions of our study.
Helix-Coil Transitions in
DNA by Novel Pt(II) Complexes: A pH Melting Study
R. Malathi1*, G. Natarajan1
and Eggehard Holler2
1Department of Genetics, Dr. AL Mudaliar Post Graduate Institute
of Basic Medical Sciences, Taramani Campus, University of Madras,Taramani,
Chennai-600 113, India
2Instiut für Biophysik und Physikalische
Biochemie, Universität Regensburg, D-93040 Regensburg, Germany
*Author to whom correspondence should be addressed. Phone: 00-91-44-492-5317;
Fax: 00-91-44-492-6709
Abstract
Recent reports have shown that pH could also be used as a melting factor to monitor helix-coil transitions in DNA; the results being comparable to those obtained by Tm studies. The rapidity with which the method can be performed to obtain similar transition curves, and elimination of the evaporation factor (at high temperatures as seen in Tm studies) is one of the advantages offered by this technique. With regard to its suitability in studying DNA-drug interactions, the addition of platinum (II) complexes changed the Pm (pH of melting) in a predictable manner thereby confirming the destabilization of bases in DNA.
In the present study, melting profiles of calf thymus DNA modified by certain chloro substituted platinum complexes have been generated using pH as a denaturing factor. These novel platinum complexes have been recently shown to have potential tumour inhibiting properties too. Diammine diaqua platinum (active form of the anti tumour drug cisplatin) was coupled to beta poly-L-malate (a bioresorbable polymer synthesized by a myxomycete), L-malate and L-succinate. At a constant Pt:P ratio (0.2), the extent of damage to DNA by these complexes in comparison to cisplatin was cisPt>SuccPt>MalPt>PMA-Pt>carboplatin. Given the similarity of the side groups of these platinum compounds with that of carboplatin (a successful second generation analog of cisplatin), interesting variations have been obtained in the DNA melting profiles, the implications of which have been discussed in the present study.
Anti-Syn Conformational Range of Pyrimidines with Deoxyribofuranose
Karen Wiechelman and Eric R. Taylor*
Department of Chemistry, University of Southwestern Louisiana, Lafayette,
LA 70504-4370
*Author to whom correspondence should be addressed. Phone: 318-482-6738;
Fax: 318-482-5676; E-mail: ert5405@usl.edu
Abstract
The ability of pyrimidine bases to adopt the syn conformation in DNA has been investigated. The distances between atoms on the sugar and base and the resulting steric energies have been calculated as a function of glycosidic torsion angle for the principal sugar puckers of the deoxyribose of cytosine. The results indicate that pyrimidines can assume both the anti and syn conformations for the 3E, 4E, 1E, 2E, 3E sugar puckers and syn for the 2E sugar pucker. For these sugar puckers the difference between the minimum energies of the anti and syn conformations is in the range of 0.1-2.0 kcal/mole, with the minimum syn energy being lower in the case of the 4E, 1E and 2E sugar puckers. It is particularly significant that cytosine can assume the syn conformation for the 3E sugar pucker commonly observed for the syn nucleotides in Z-DNA with both alternating pyrimidine/purine (APP) and non-APP sequences. The results of this investigation confirm that steric interactions resulting from putting a pyrimidine nucleotide in the syn conformation are not a major factor in the preference for APP base sequences in Z-DNA.