PubMed Health⌕ Search

Biomedical subjects

B Pullman

Publications and source records attributed to B Pullman.

At least 19 recordsLinked to original sources
PubMed1991

Sequence specificity in the binding of anti-tumour anthracyclines to DNA: a success of theory.

Up to 1985 apparent contradictions in the results of experimental investigations on the possible sequence specificity in the interaction of the two fundamental antitumour anthracyclines, daunomycin and Adriamycin, with DNA have led to an intellectually confused situation and serious doubts about the existence of any such specificity. Theoretical studies carried out in our laboratory in 1985 demonstrated that these failures were due to the attempt to relate the specificity exclusively to the nature of the two base pairs of the intercalation site. We have shown that a definite specificity can in fact be established but only at the level of triplets of base pairs, comprising in addition to the base pairs of the intercalation site, the neighbouring base pair at the 5' side. Our explicit predictions indicate the preferred triplets G-C, C-G, T-A or G-C, C-G, A-T with the intercalation site between the two GC base pairs, followed relatively closely by the A-T, C-G, T-A triplet with the intercalation site between the AT and CG base pairs. Subsequent extensive experimentation carried out in a number of laboratories confirmed the validity of our concept and the exactitude of our predictions, although some controversy persists among experimentalists as to the nature of the most preferred triplet.

Antibiotics, Antineoplastic↗
PubMed1990

Modelling of the binding specificity in the interactions of cationic porphyrins with DNA.

A theoretical investigation is performed of the complexes of a tetracationic porphyrin, tetra-(4-N-methylpyridyl)-porphyrin, (T4MPyP), with the hexanucleotides d(CGCGCG)2 and d(TATATA)2, considering the possibility of both the intercalative and the groove binding interactions. These computations demonstrate that T4MPyP manifests a significant preference for intercalation in its complex with d(CGCGCG)2 but for non intercalative binding in the minor groove in its complex with d(TATATA)2. Such a dual binding behaviour of T4MPyP as a function of the sequence to which it is attached is fully consistent with available experimental data. It demonstrates that intercalation and groove binding may be viewed as two potential wells on a continuous energy surface. In agreement with experiment, the computations indicate that in the here considered case the deepest well is associated with intercalation.

Base Sequence↗
PubMed1989

Modelling basic features of specificity in the binding of a dicationic steroid diamine to double-stranded oligonucleotides.

An investigation of the intrinsically preferred binding modes of a steroid diamine, dipyrandium, to the double-stranded hexanucleotides d(TATATA)2, d(ATATAT)2, and d(CGCGCG)2 is carried out by the energy minimization procedure JUMNA. Several alternative binding modes are compared: groove binding in which the conformation of the oligonucleotide remains close to that of B-DNA, intercalation between base-pairs and interaction with variously kinked structures in which base pairs of dinucleoside steps open towards the groove in which the binding occurs. The favored binding configuration occurs at the d(TpA) step of the AT kinked nucleotides in which the kink opens the base pairs towards the minor groove. Thus, for the d(T1A2T3A4T5A6)2 sequences the preferred complexation involves the kink at the T3A4 step facing the cyclohexane rings A, B, and C of the ligand. For the d(A1T2A3T4A5T6)2 sequence, the kink occurs at the T2A3 step facing the cationic pyrrolidine ring linked to ring A. The binding of dipyrandium to d(CGCGCG)2 is found to be considerably less favourable than for either of the two (AT) sequences.

Algorithms↗
PubMed1989

Modelling basic features of specificity in DNA-aureolic acid-derived antibiotic interactions.

The nonintercalative groove binding of a simplified model of olivomycin, to sequences d(CGCGCGC)2, d(TATATAT)2, and d(CICICIC)2 is investigated. A significant preference is displayed for the minor groove of the d(CG) sequence. This is due predominantly to the formation of H-bonds between the hydroxyl groups on the aglycone of the drug and the 2-amino group of the central guanine of the oligonucleotide.

Base Sequence↗
PubMed1989

Theoretical modeling of DNA-monocationic lexitropsin complexation: influence of ligand binding on DNA curvature.

A theoretical study is presented on the complexation to DNA of a monocationic lexitropsin. Energetics and the structures of the complexes formed are analyzed for three base pair sequences of a nucleic acid octamer. The influence of the ligand binding on the nucleic acid conformation is analysed in detail. It is found that whereas the uncomplexed nucleic acid segments have very irregular structures with an overall curvature varying between 15 degrees and 20 degrees, the DNA structure becomes more regular and the curvature is strongly reduced upon the binding of a monocationic lexitropsin.

Computer Simulation↗
PubMed1989

Joint experimental and theoretical investigation of the comparative DNA binding affinities of intercalating anthracycline derivatives.

The comparative binding affinities for poly(dA-dT) and poly(dG-dC) of novel antitumor anthracyclines are reported. The data concern, besides the parent compound adriamycin (ADM), 4-demethoxy 6-deoxy 6-aminodaunomycin (II), 9-deoxy-ADM (III), 4-demethyl-6-O-methyl-ADM (IV), and 3'-deamino-3'-hydroxy-4'-epi-ADM (IV). Theoretical computations are performed in parallel for their comparative binding affinities to model double-stranded hexanucleotides, d(GCGCGC)2, d(TATATA)2, and d(CGTACG)2, using the SIBFA (sum of interactions between fragments computed ab inito) procedure. The computations reproduce in a very satisfactory manner the most salient features of the experimental comparative binding affinities. These encompass, in particular, a higher affinity for the d(TATATA)2 oligomer of II than that of ADM, despite the absence of the 14-OH substituent in II, a marked reversal of the CG versus TA sequence selectivity of the neutral compound V, favoring the d(CGCGCG)2 oligomer over the d(TATATA)2 one; and the deleterious effect incurred on the binding affinities by the presence of an O-methyl substituent at position 6 of the chromophore.

Antibiotics, Antineoplastic↗
PubMed1988

Energetics and stereochemistry of DNA complexation with the antitumor AT specific intercalators tilorone and m-AMSA.

Computations by the SIBFA method on the intercalative interaction energies of tilorone and m-AMSA with B-DNA representative oligonucleotides account for the specificity of these antitumor drugs for AT sites and minor groove intercalation. In tilorone this specificity is due to the strong preference of the side chains for the minor groove, which overcomes the preference of the chromophore for a GC intercalation site. In m-AMSA the specificity is due to the combined preference of both the chromophore and the anilino side chain for AT intercalation site and minor groove, respectively. o-AMSA is shown to manifest a similar (although significantly less pronounced specificity) as m-AMSA but a higher affinity for DNA. A comparison of the energetics and stereochemistry of intercalative binding to DNA of m-AMSA (AT minor groove specific) and 9-aminoacridine-4-carboxamide (GC major groove specific), which possess the same chromophore and differ only by the nature and position of the side chains, shows the possibility of important variations in the intercalative behaviour of chromophoric drugs as a function of the substituent groups attached to them.

Amsacrine↗
PubMed1988

Theoretical study of the sequence selectivity of isolexins, isohelical DNA groove binding ligands. Proposal for the GC minor groove specific compounds.

A theoretical study is presented of complex formation between DNA fragments of different base sequences and isolexins, "isohelical base reading polymers", formed of heteroaromatic pentagonal rings joined by appropriate linkers. Extensive computations are performed for the isolexin composed of the furan-pyrrole-furan sequence. They involve charged ligands with propioamidinium groups at both ends as well as neutral molecules with terminal methyl, carbonyl and amino groups. Two different groups (C = O and NH) are used as linkers between the base reading moieties. The role of these elements on the binding preference of the ligands has been examined. The results show that the mere possibility of formation of hydrogen bonds between a ligand and the nucleic acid bases is not sufficient to ensure its binding specificity which is determined largely by the interplay of electrostatic factors. Thus the dicationic isolexins uniformly prefer AT sequences. For the neutral isolexins the nature of the groups forming the linkers is a major factor in defining the specificity, although these groups do not participate directly in the interaction with DNA. The C = O linkers favour binding to AT sequence while the N-H linkers permit preferential binding to the GAG sequence. Finally, for the first time in theoretical computations, a ligand is proposed which should bind preferentially to the minor groove of GC sequences: this ligand is a neutral isolexin composed of three furan rings linked by two N-H groups. This ligand is considered as an improvable prototype. Altogether the results presented open the path for the designing of minor groove ligands specific for any desirable DNA base sequence.

Base Sequence↗
PubMed1988

Drug recognition of DNA. Proposal for GC minor groove specific ligands: vinylexins.

In a previous publication in this journal we have proposed an isolexin-like prototype of a GC minor groove specific ligand. The present paper is devoted to refinements of this prototype (increase in specificity and in DNA binding energy). It is shown that only a very limited improvement can be obtained by increasing the proton accepting capabilities of the heteroaromatic ring systems of the prototype, although these rings interact directly with the proton donating NH2 group of guanine. On the other hand a significant increase both in GC specificity and in DNA binding energy is obtained by replacing the NH linkers of the isolexin by C = C double bonds (yielding what we term "vinylexins"). Specificity is still largely conserved and the DNA binding energy is significantly increased in monocationic vinylexins, which should thus be efficient GC minor groove specific ligands. The outstanding importance for the GC specificity of the C = C linkers is evidenced by the disappearance of this specificity when these linkers are replaced by peptide bonds (peptilexins). On the other hand vinylexins with proton donating heteroaromatic rings are, as expected, AT specific. The vinylexin family may thus represent universal minor groove binding agents susceptible to bind to any given base pair sequence of DNA, following the positioning of their proton donor and proton acceptor rings. This study confirms the insufficiency of purely geometrical and/or hydrogen bonding considerations for the correct estimation of GC versus AT specificity of groove binding ligands. These can only be accounted for by taking into consideration the overall electronic properties of the interacting species and explicitly calculating the energies of complex formation including all the relevant contributions.

Base Sequence↗
PubMed1987

Theoretical study of the sequence specificity in the covalent binding of the antitumor drug CC-1065 to DNA.

A theoretical modelling is presented of the covalent adducts of the antitumor agent CC-1065 with B-DNA. The optimal complexes are obtained by energy minimisation, taking into account full structure flexibility, including the flexible rings of the ligand and DNA. The binding preference of CC-1065 with respect to base sequence is studied. The results obtained elucidate the origin of the preference for two AT base pairs on the 5'side of the modified adenine. The modifications of the DNA structure upon ligand covalent binding are discussed.

Antibiotics, Antineoplastic↗
PubMed1987

A tentative model of the intercalative binding of the neocarzinostatin chromophore to double-stranded tetranucleotides.

Theoretical computations are performed of the intercalative binding of the neocarzinostatin chromophore (NCS) with the double-stranded oligonucleotides d(CGCG)2, d(GCGC)2, d(TATA)2 and d(ATAT)2. Minor groove binding is preferred over major groove binding. It is found that the long axis of the stacked naphtoate ring lies approximately parallel to the long axis of the base pairs of the intercalation site. The galactosamine ammonium group interacts with specific sites of the groove (O2/N3 of bases 2 and O1' of sugar S3), whereas the dodecadyine ring system wraps around the groove towards the backbone. An overall AT versus GC preference is derived. Intercalation in a central purine-(3', 5')-pyrimidine sequence appears to be preferred over that in a central pyrimidine-(3', 5')-purine sequence.

Antibiotics, Antineoplastic↗
PubMed1987

A theoretical study of the sequence specificity in binding of lexitropsins to B-DNA.

A theoretical study is presented on the binding to B-DNA of a series of lexitropsins, these ligands being netropsin derivatives in which one or both of the pyrrole rings have been replaced by imidazoles. The best complexes have been located by energy minimisation taking into account nucleic acid flexibility, ligand flexibility, explicit, mobile counterions and solvent dielectric effects. Calculations have been performed for two homopolymeric DNA receptor sequences, AT base sequence, which only decreases in the imidazole derivatives. These results emphasize the decisive role of the molecular electrostatic potential of the nucleic acid in determining the sequence selectivity of these ligands, as opposed to the postulated role of adenine C2 - pyrrole beta hydrogen contacts.

Base Sequence↗
PubMed1987

Sequence selectivity, a test of the nature of the covalent adduct formed between benzo[a]pyrene and DNA.

A theoretical study is presented of the energetic and structural properties of covalent adducts of benzo[a]pyrene and a DNA fragment. Energy optimisation is performed with the use of minimiser with constraints and an advanced semiempirical energy formula. Three types of adducts are studied: an external complex with the benzopyrene located in the DNA minor groove and two types of intercalative complexes with the carcinogen situated on the 3' side and 5' side of the covalently bound guanine. For each of the adducts the effects of DNA base sequence are examined. It is shown that the results for the intercalative complex with the carcinogen situated on the 5' side of the modified guanine correlate with the experimentally determined sequence preference.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

A theoretical study of the intercalative binding of the anti-tumour drug anthrapyrazole to double-stranded oligonucleotides.

Theoretical computations have been performed on the intercalative binding of anthrapyrazole to the double-stranded tetranucleotides d(GCGC)2 and d(ATAT)2, intercalation taking place in the central pyrimidine-(3',5')-purine sequences, with an unwinding angle of 29 degrees. The complex is principally stabilized by hydrogen-bonds of the two side chains with the ionic oxygens of the two central phosphates. In marked contrast with the corresponding complexes of the related compound mitoxantrone, the N7 atoms of the two central purines do not participate in hydrogen-bonding interactions with the dimethylamino fragments of the side chains. Side chain A of the anthrapyrazole, which is on the imino nitrogen side, is located farther away from the core of the major groove, closer to the phosphate backbone. Compared to the mitoxantrone complexes, there is a considerable decrease in the difference of interaction energy between the d(GCGC)2 and the d(ATAT)2 complexes. This is in line with the experimental results indicating that, compared to mitoxantrone, anthrapyrazole manifests little or no GC sequence selectivity.

Anthracyclines↗
PubMed1986

Theoretical studies on the interaction of proteins and nucleic acid. II. The binding of alpha-helix to B-DNA.

Interactions between B-DNA and homopolymeric alpha-helices of glycine, alanine, serine, asparagine and aspartic acid have been studied theoretically. The complexation energy has been minimised taking into account the interactions between DNA and the polypeptides as well as the internal energy of the alpha-helix and the interaction energy of counterions with the complex. The results obtained indicate the important role of strong hydrogen bonds between the peptide side chains and nucleic acid phosphate groups, these bonds being much stronger than specific interactions with the base-pairs. The formation of these structural bonds depends on the size of the alpha-helix, which in turn determines whether bridging across the major groove is possible. The steric role of the methyl group of thymine in orienting the peptide helix and the role of DNA screening cations in complex stabilization are also significant.

DNA↗