Intramolecular hydrogen bond-controlled prolyl amide isomerization in glucosyl 3(S)-hydroxy-5-hydroxymethylproline hybrids: a computational study.

Peptide mimics containing spirocyclic glucosyl-(3(S)-hydroxy-5(S)-hydroxymethyl)proline (1) and glucosyl-(3(S)-hydroxy-5(R)-hydroxymethyl)proline (2) hybrids differing in the stereochemistry of the polar hydroxymethyl substitutent at the C-5- or (C(delta))-position have been investigated computationally. A computational "build and search" protocol of molecular mechanics systematic search/Monte Carlo search, followed by density functional theory (DFT), has been developed to ensure complete coverage of the large conformational space. Gas-phase DFT optimizations at the B3LYP level of theory lead to a strong preference for the cis conformation in the prolyl amide bond for both compounds 1 and 2. However, inclusion of the solvent water by means of continuum solvation (PCM) results in a reduction of the prolyl amide cis population in both compounds, leading to good agreement with previous experimental observations. Intramolecular hydrogen bonding involving the C-5-hydroxymethyl substitutent is seen to play a crucial role to tune the thermodynamics of prolyl amide cis/trans isomerization and is responsible for the high cis prolyl amide population in compound 2. Our results indicate that H-bond-forming substituents like the hydroxymethyl group at the C-5-position in proline can be used to control cis/trans prolyl amide isomerization. High cis prolyl amide conformer populations can be achieved by proper choice of the stereochemistry at the C-5-position.

Intramolecular hydrogen bond-controlled prolyl amide isomerization in glucosyl 3'(S)-hydroxy-5'-hydroxymethylproline hybrids: influence of a C-5'-hydroxymethyl substituent on the thermodynamics and kinetics of prolyl amide cis/trans isomerization.

Peptide mimics containing spirocyclic glucosyl-(3'-hydroxy-5'-hydroxymethyl)proline hybrids (Glc3'(S)-5'(CH(2)OH)HypHs) with a polar hydroxymethyl substituent at the C-5' position, such as C-terminal ester Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe and C-terminal amide Ac-Glc3'(S)-5'(CH(2)OH)Hyp-N'-CH(3), were synthesized. C-Terminal esters exhibit increased cis population (23-53%) relative to Ac-3(S)HyPro-OMe (17%) or Ac-Pro-OMe (14%) in D(2)O. The prolyl amide cis population is further increased to 38-74% in the C-terminal amide form in D(2)O. Our study shows that the stereochemistry of the hydroxymethyl substituent at the C-5' position of proline permits tuning of the prolyl amide cis/trans isomer ratio. Inversion-magnetization transfer NMR experiments indicate that the stereochemistry of the hydroxymethyl substituent has a dramatic effect on the kinetics of prolyl amide cis/trans isomerization. A 200-fold difference in the trans-to-cis (k(tc)) isomerization and a 90-fold rate difference in the cis-to-trans (k(ct)) isomerization is observed between epimeric C-5' 3 and 4. When compared to reference peptide mimics Ac-Pro-OMe and Ac-3(S)Hyp-OMe, our study demonstrates that a (13-16)-fold decrease in k(tc) and k(ct) is observed for the C-5'(S), while a (5-24)-fold acceleration is observed for the C-5'(R) epimer. DFT calculations indicate that the pyrrolidine ring prefers a C(beta) exo pucker in both Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe diastereoisomers. Computational calculations and chemical shift temperature coefficient (Delta delta/Delta T) experiments indicate that the hydroxymethyl group at C-5' in Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe forms a stabilizing intramolecular hydrogen bond to the carbonyl of the N-acetyl group in both epimeric cis isomers. However, a competing intramolecular hydrogen bond between the hydroxymethyl groups in the pyrrolidine ring and pyran ring stabilizes the trans isomer in the C-5'(S) diastereoisomer. The dramatic differences in the kinetic properties of the diastereoisomeric peptide mimics are rationalized by the presence or absence of an intramolecular hydrogen bond between the hydroxymethyl substituent located at C-5' and the developing lone pair on the nitrogen atom of the N-acetyl group in the transition state.

Mixed uranium chloride fluorides UF6-nCln and methoxyuranium fluorides UF6-n(OCH3)n: a theoretical study of equilibrium geometries, vibrational frequencies, and the role of the f orbitals.

The title compounds, the uranium (VI) fluoride chlorides (UF6-nCln, n = 0-6) and methoxyuranium (VI) fluorides [UF6-n(OCH3)n, n = 0-5], have been studied using relativistic density functional theory. Applying the B3LYP hybrid functional and an effective core potential on uranium, equilibrium geometries have been calculated for these molecules. In addition, harmonic vibrational frequencies have been computed for the chloride fluorides. Calculated frequencies have been compared to experiment where possible. All experimentally observed bands have been assigned, based on these calculations. The average deviation between theoretical and experimental frequencies is 15.6 cm-1 for 23 experimental modes. Theory always underestimates the experimental frequencies. This can be explained by the calculated bond lengths that are somewhat too long. The electronic structure of the uranium (VI) chloride fluorides has been investigated using scalar relativistic calculations and the PW91 functional. Periodic trends in the role and bonding contribution of the uranium 5f orbitals are discussed.

[Post-traumatic meningitis due to Pasteurella multocida]. / Posttraumatische Meningitis durch Pasteurella multocida

The clinical data of a 14-year old female patient with posttraumatic meningitis by Pasteurella multocida are reported. The behaviour of the isolated strain is recorded in cultural and biochemical aspect as well as in animal experiment. The importance of the infection with Pasteurella multocida is lined out and the possible origin of the disease in the reported case is discussed. Finally some problems of special bacteriological diagnosis are explained and hints are given in this respect.