Stefan Naumann

Ab initio and DFT calculations on the initial step in thiamin catalysis

Abstract The diphosphate ester (ThDP) of thiamin (vitamin B 1 ) is an important cofactor of enzymes within the carbohydrate metabolism. The initial reaction step shared by all ThDP-dependent enzymes is the deprotonation of the C2–H of the thiazolium ring. The replacement of the 4′-amino group by a hydroxyl one in the pyrimidine ring leads to the oxy-ThDP analogue which is known as an antagonist in thiamin catalysis. Ab initio and DFT calculations on the MP2/6-31G* and B3LYP/6-31G* level were performed to study the proton relay function in thiamin and oxythiamin systems. Both MP2 and B3LYP calculations show significant differences of the reaction coordinate of the ylide formation in the systems. Tautomers, protonated and deprotonated species of both systems show different trends regarding their stability. The influence of correlation effects on the results is discussed by comparison with the HF-SCF/6-31G* data. Frequency calculations on the B3LYP/6-31G* level were performed to characterize the minima and transition state structures, respectively.

Theoretical studies on the structure of chiral 1,2-diol systems. Monomers, dimers and monohydrates

Abstract The structures and stabilities of the isolated 1,2-propanediol (PDL1,2) monomers, dimers and monohydrates were investigated by the force field versions PIMM91 and GROMOS87 as well as the semiempirical PM3 method. The results on the PDL1,2 monomers are in agreement with ab initio data and gas phase experimental findings and show that the most stable conformers are stabilized by internal hydrogen bonding. The preferred structures of the dimers are characterized by the formation of additional intermolecular hydrogen bonds. Within the calculations dimers of PDL1,2 generated from the same (R-R) and different (R-S) enantiomers are taken into account. The aim of the investigations on the monohydrates of PDL1,2 was to study the function of water at the association of the 1,2-diol head groups in bilayers with a very simple model. Results on 1,3-propanediol are included for comparison. The different energetic and structural behaviours of both diol groups are discussed with respect to the formation of intramolecular and intermolecular hydrogen bonds.

A Structure-Function Study of Nucleic Acid-Fluorenone Complexes

Abstract Several 2,7-bis-[(dialkylamino)-acetylamino]-fluoren-9-one derivatives (fluoramides) were synthesized as analogues of the DNA binding compound tilorone (2,7-bis[(diethylamino)-ethoxy]-fluoren-9-one). Previous studies showed the drugs to induce cytokines and inhibit reverse transcription. Here, their binding to DNA was evaluated using UV and circular dichroism studies. Like tilorone, the fluoramides derivatives also intercalate resulting in increased Tm values and new CD signatures. A preference to alternating A-T and G-C sequences was detected; only minor interaction to homologous sequences was observed. Moreover, no upper limit in the drug/DNA ratio was found, testing limit being the precipitation of the drug. However, surface plasmon resonance (SPR) studies of tilorone and 2,7-bis-[(dipropylamino)-acetyl-amino]-fluoren-9-one, indicate an astonishing drug/base pair ratio (r > 1), which point to a multitude of interactions under SPR conditions. Molecular modeling calculations, where the geometries of the complexes optimized under the assumption of intercalative and multitude of suprahelical arrangements, rationalize the observations. Based on the thermodynamic and biological studies, a structure-function model is proposed.

GROMOS-MD SIMULATIONS ON 1,2-DIOL WATER CLUSTERS

Abstract The structure, stability and dynamics of clusters of amphiphilic 1,2-octanediol, phenyl and cyclohexyl substituted 1,2-ethanediols as well as 1,2-hexadecanediol in the gas phase and aqueous solution were investigated. For the molecular dynamics simulations the program package gromos 87 was used. Such diols are suitable as model systems for the study of the structural formation in amphotropic liquid crystals and bilayers. First results of MD simulations on clusters up to 64 diol molecules are presented. Especially, the role of hydrogen bonding as well as the function of water molecules in the process of association of the hydrophilic head groups were studied in more detail. Moreover, the influence of modifications in the hydrophobic part on the molecular aggregation was investigated. For the visualization of the MD results a graphics tool was created on workstations.

Biomesogenic matrix systems.

Abstract The bifunctionally reactive nucleoside and distant nucleoside analogs adenosine (Ado), S-[(adenine-9-yl)methoxyethyl]-L-cysteine (Na-salt) (cysA) and 9-vinyladenine (vA) in aqueous solutions assemble on complementary polyuridylic acid templates to form complex lyomesophases. The systems are investigated by polarizing microscopy, differential scanning calorimetry (DSC) and 1H- and 31P-nmr spectroscopies, assisted by molecular modeling studies. The results indicate the importance of biomesogenic (pre)ordering in nucleic acid native and artificial matrix reactions.

GROMOS-MD SIMULATIONS ON BIAMPHIPHILIC TETRAOL CLUSTERS

The structure, stability and dynamics of clusters of biphenyl substituted biamphiphilic tetraol systems in the gas phase were investigated by molecular dynamics simulations. For the MD simulations the program package GROMOS87 has been used. Such doubleheaded 1,2-diol-based molecules are suitable model systems for the study of the structural formation in amphotropic liquid crystals and bilayers. The results of MD simulations on clusters up to 64 tetraol molecules are presented. Especially, the function of the hydrogen bonding in the process of association of the hydrophilic head groups was studied. The influence of 2,3-dihydroxy-propyl and -propyloxy head groups as well as the temperature dependence on the molecular aggregation was investigated in more detail.