PubMed · 16518382
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Nicholas Furnham, Tom L Blundell, Mark A DePristo, Thomas C Terwilliger. 2006. Is one solution good enough?. https://doi.org/10.1038/nsmb0306-184
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The synthesis, structures, and optical and electrochemical properties of meso-phosphorylporphyrins are described. The copper-catalyzed carbon-phosphorus cross-coupling reaction of a meso-iodoporphyrin with di-n-butyl phosphite and diphenylphosphane oxide has proved to be an efficient and general method for the synthesis of meso-phosphorylporphyrins. Zinc phosphorylporphyrins thus obtained readily undergo self-organization through P-oxo-Zn coordination to form noncovalently linked, cofacial porphyrin dimers or linear oligomers, which have been characterized by spectroscopic methods and X-ray crystallographic analyses. In toluene, CH(2)Cl(2), and CHCl(3), the zinc phosphorylporphyrins exist mostly as dimers or monomers, depending on their concentrations, the temperature, and the presence of additives. The self-association constants for dimerization in toluene have been determined by UV/Vis absorption titration measurements. The meso-diphenylphosphorylporphyrin dimer displays excitonic coupling of the Soret band with a splitting energy of 940 cm(-1). Fluorescence lifetimes of the zinc phosphorylporphyrins have been found to be affected only slightly by the concentration of the solution, and by the addition of triphenylphosphane oxide, suggesting that the effect of dimerization on their photodynamics in the S(1) state is negligible. On the other hand, the effect of dimerization is clearly reflected in their electrochemical oxidation processes, as the initially produced radical cations are efficiently delocalized over the two porphyrin rings. These findings demonstrate the potential utility of meso-phosphorylporphyrins as new models for the special pair in photosynthesis and as new building blocks for porphyrin-based supramolecular materials.
Increasing attention is being paid to the role of selenium, both as an essential component required for the activity of many enzymes and in the context of selenium-based pharmaceutical agents. A wide range of therapeutics that include selenium are on the market and under development, such as antihypertensive, anticancerogenic, antiviral, and immunosuppressive agents. Computer-aided drug design (CADD) has proven to be an important tool for the development of new drugs. Many CADD techniques, including docking, molecular dynamics simulation, and other receptor-based approaches, require an accurate understanding of the nature of the intermolecular forces that act to stabilize protein-ligand complexes; moreover, a quantitative assessment of these interactions furthers our efforts to rationalize the drug design process. In this paper, we consider one class of interaction involving selenium, that between Se and aromatic rings. Prior work has shown that interactions between divalent sulfur and aromatic rings are observed much more frequently than would be expected on the basis of chance, both in protein structures and the crystal structures of organic compounds that include these moieties. Recent studies on the optimization of inhibitor-protein binding also suggest that sulfur-aromatic interactions are important in stabilizing these complexes and may be crucial focal point for CADD. Given that selenium and sulfur have similar chemistry, and that selenium is significantly more polarizable, we propose that Se-aromatic interactions may also play an important stabilizing role in the structure of folded proteins and in drug-protein complexes. We have tested this hypothesis against data from the Cambridge Crystallographic Database and ab initio quantum chemical calculations. We have found evidence that selenium does interact strongly with aromatic rings and may play a role analogous to sulfur in stabilizing protein folds. In addition, selenium should be considered along with sulfur in rational drug design strategies that seek to improve binding to target protein sites that include aromatic rings.
DHDPS (dihydrodipicolinate synthase) catalyses the branch point in lysine biosynthesis in bacteria and plants and is feedback inhibited by lysine. DHDPS from the thermophilic bacterium Thermotoga maritima shows a high level of heat and chemical stability. When incubated at 90 degrees C or in 8 M urea, the enzyme showed little or no loss of activity, unlike the Escherichia coli enzyme. The active site is very similar to that of the E. coli enzyme, and at mesophilic temperatures the two enzymes have similar kinetic constants. Like other forms of the enzyme, T. maritima DHDPS is a tetramer in solution, with a sedimentation coefficient of 7.2 S and molar mass of 133 kDa. However, the residues involved in the interface between different subunits in the tetramer differ from those of E. coli and include two cysteine residues poised to form a disulfide bond. Thus the increased heat and chemical stability of the T. maritima DHDPS enzyme is, at least in part, explained by an increased number of inter-subunit contacts. Unlike the plant or E. coli enzyme, the thermophilic DHDPS enzyme is not inhibited by (S)-lysine, suggesting that feedback control of the lysine biosynthetic pathway evolved later in the bacterial lineage.