Biomedical subjects
Publications and source records attributed to B Pullman.
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The paper presents the results of computation of the electrostatic potential and steric accessibility of the B-DNA self-complementary dodecamer CGCGAATTCGCG following the geometry of the recent single crystal structure of Dickerson et al. This structure shows significant variations from classical B-DNA; their influences on the calculated properties are discussed. The results are related to general features of hydration of the crystal. A particularly significant general finding concerns the greater negative potential in the center of the oligonucleotide helix than at its extremities. This will be a general feature of such short helices, independent of their base sequence. It may have important implications for the reactivity of DNA oligomers.
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The sites of the 76 nucleic acid bases of tRNAPhe potentially reactive towards electrophiles are studied by calculations on the associated molecular electrostatic potentials and the static steric accessibilities. Each of these sites is treated in its environment within the macromolecule. The influence of various schemes of screening by countercations of the backbone phosphates on the electrostatic potentials is investigated. The possible significance of the potentials and accessibilities in connection with observed chemical reactivities is discussed.
In order to account for the specificity of binding of tetramethylammonium (TMA) versus monomethylammonium (MMA) to the combining site of phosphorylcholine specific immunoglobulin IgA H-8, theoretical computations are performed on the interaction energies of these cations with varying combinations of amino acid side chains, present or suspected to be present at that site. The dehydration of the cations, which represents a prerequisite for their binding is about 20 kcal/mol more difficult for MMA than for TMA. The interaction energies with the binding site are somewhat higher for MMA than for TMA. For some combinations of the amino acid side chains, their difference is smaller than the difference in the dehydration energy. Such combinations ensure preferential binding of TMA.
A theoretical study of indices potentially useful for investigation of the reactivity of the recently discovered Z-DNA double helix is presented. The electrostatic potential minima and the steric accessibility of reactive sites are calculated. The effect of screening the phosphate groups by metal cations is investigated. The results are compared with those for the B-DNA double helix.
Quantum-mechanical computations are performed on the in vacuo and in water interactions between the purine bases guanine and cytosine and the side chains of the amino acids arginine, lysine, glutamic acid and glutamine. The results predict that while guanine should be the more strongly interacting base both in vacuo and in water, lysine should be the most strongly interacting amino acid in vacuo and arginine the most strongly interacting amino acid in water solvent. The theoretical results on the interactions in water agree satisfactorily with experimentation.
We present a preliminary theoretical study of the electrostatic potential surrounding yeast tRNAPhe by computing the component of this potential due to all the 76 phosphate groups of the molecule. The general features of the results obtained are discussed and deductions concerning the binding of Mg2+ ions to the molecule in relation to the potential are presented.
The evaluation of the electrostatic molecular potential at important nucleophilic sites of the purine and pyrimidine bases in poly (dG.dC) and poly (dA.dT) and of the evolution of the potential through the series free bases-nucleosides-nucleotides-single polynucleotide helices-double helices enables the interpretation of the evolution of the corresponding reactivity of the bases towards a series of electrophilic carcinogenic and mutagenic reactants.
Arguments are presented which show that conformations II and III proposed by Lee and Tinoco [Lee, C.H., and Tinoco, I., Jr. (1977), Biochemistry 16, 5403] for ribodinucleoside monophosphates in aqueous solution are untenable. It has been shown that ribodinucleoside monophosphates exist in aqueous solution as an equilibrium blend of the classically recognized right-handed stack (g-g-), loop stack (g+g+), skewed (g+t), and extended arrays. In order to determine the effect of epsilonA base on the conformer distribution in the equilibrium blend, detailed ring-current calculations were performed and the isoshielding curves for epsilonA were derived. Use of these curves vis-a-vis dimerization shift data indicates that introduction of epsilonA perturbs the equilibrium blend which causes an increase in the population of skewed (g+t) arrays.
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The quantum mechanical PCILO method has been applied for the determination of conformational properties of 8-amino- and 8-dimethylaminoadenosine 5'-monophosphate. Contrary to other 8-substituted nucleotides the amino derivative shows a preference for an anti arrangement about the glycosidic bond. This conformation is stabilized by an intramolecular hydrogen bond between the purine and the exocyclic group. 8-dimethylamino-adenosine-5'-monophosphate adopts the syn conformation with slightly rotated dimethylamino group. There is, however, a local minimum for the anti form associated with the unusual value of chiCN = 300 degrees. This minimum is probably populated when the nucleotide is bound to lactate dehydrogenase apoenzyme. No particularly strong interactions are necessary for the stabilization of the anti form. The computations account satisfactorily for the available experimental data.
PCILO (perturbative configuration interaction using localized orbitals) computations have been carried out for the conformational properties of 8-azapurine nucleosides. The results indicate an anti conformation for Xcn and a gg conformation for phiC(4')-C(5') for C(2')-endo 8-aza analogs compared to the syn and gg conformation for the corresponding purine nucleosides. For C(3')-endo sugar puckering, both molecules prefer the syn conformation due to intramolecular hydrogen bonding between O(5')-H of the sugar and N(3) of the base, the preference being more profound in 8-aza analogs. The crystallographic conformation 8-azaadenosine has been attributed to crystal forces. The available NMR data on 8-azapurine nucleosides are in agreement with the PCILO predictions.
The PCILO method has been used for a theoretical exploration of the conformational properties of tRNAPhe with respect to the phosphodiester torsion angles. The computations were based on the utilisation of the dinucleoside triphosphate model and took into account the different combinations of sugar puckers and different conformations about the C4'-C5' bond. The dependence of the (omega'-omega) conformational energy maps upon these factors was specified. A detailed comparison is carried out between the theoretical results and experimental data on the crystal structure of tRNAPhe produced by four different groups of investigators.
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