Biomedical subjects

Roger A Klein

Publications and source records attributed to Roger A Klein.

5 recordsLinked to original sources

PubMed2004

Barriers to internal rotation around the C-N bond in 3-(o-aryl)-5-methyl-rhodanines using NMR spectroscopy and computational studies. Electron density topological analysis of the transition states.

We have investigated the pairs of rotational isomers for six 3-(o-aryl)-5-methyl-rhodanines (Z = H, F, Cl, Br, OH, and CH3) using NMR spectroscopy and density functional theory (DFT) calculations. Electron density topological and NBO analysis has demonstrated the importance of non-covalent interactions, characterised by (3, -1) bond critical points (BCPs), between the oxygen and sulfur atoms on the thiazolidine ring with the aryl substitutents in stabilizing the transition states. The energetic activation barriers to rotation have also been determined using computational results; rotational barriers for 3-(o-chlorophenyl)-5-methyl-rhodanine (3S) and 3-(o-tolyl)-5-methyl-rhodanine (6S) were determined experimentally based on NMR separation of the diastereoisomeric pairs, and the first-order rate constants used to derive the value of the rotational barrier from the Eyring equation.

Computer Simulation↗

PubMed2003

Hydrogen bonding in diols and binary diol-water systems investigated using DFT methods. II. Calculated infrared OH-stretch frequencies, force constants, and NMR chemical shifts correlate with hydrogen bond geometry and electron density topology. A reevaluation of geometrical criteria for hydrogen bonding.

Although the two hydroxyl groups in 1,2-diols interact as evidenced by NMR and IR spectroscopic shifts, electron density topological analysis has shown a bond critical point (BCP) and atomic bond path to be absent (Klein, R. A.; J Comp Chem 2002, 23, 585-599; J Am Chem Soc 2002, 124, 13931-13937), indicating that no intramolecular hydrogen bond is formed. Here, we demonstrate that small NMR or IR shifts are neither necessarily diagnostic nor sufficient as indicators of hydrogen bond formation; moreover, modified van der Waals atomic radii are needed for estimating maximum nuclear interaction distances and nuclear interpenetration.

Journal Article↗

PubMed2002

Electron density topological analysis of hydrogen bonding in glucopyranose and hydrated glucopyranose.

Topological analysis of the electron density profiles and the atomic basin integration data for the most energetically favorable (4)C(1) and (1)C(4) conformers of beta-D-glucopyranose, calculated at the B3LYP/6-31+G(d), MPWlPW91/6-311+G(2d,p), and MP2/6-31+G(d) levels, demonstrates that intramolecular hydrogen bonding between adjacent ring OH groups does not occur in glucopyranose, given the need to demonstrate a bond critical point (BCP) of correct (3,-1) topology for such an interaction to be termed a hydrogen bond. On the other hand, pyranose ring OH groups separated by three, rather than just two, carbon atoms are able to form an intramolecular hydrogen bond similar in topological properties and geometry to that found for propane-1,3-diol. Vicinal, equatorial OH groups in the (4)C(1) conformer of glucopyranose are, however, able to form strong bidentate hydrogen bonds with water molecules in a cooperative manner, each water molecule acting simultaneously as both hydrogen bond donor and acceptor, and characterized by (3,-1) bond critical points with increased values for the electron density and the Laplacian of rho(r) compared to an isolated ethane-1,2-diol/water complex.

Electrons↗

PubMed2002

The functional consequences of mis-sense mutations affecting an intra-molecular salt bridge in arylsulphatase A.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulphatase A. We describe the functional consequences of three mis-sense mutations in the arylsulphatase A gene (Asp-335-Val, Arg-370-Trp and Arg-370-Gln), affecting an apparent intramolecular Asp-335 to Arg-370 salt bridge, and interpret the effects and clinical consequences on the basis of the three-dimensional structure of arylsulphatase A. Asp-335-Val and Arg-370-Trp substitutions each cause a complete loss of enzyme activity and are associated with the most severe form of the human disease, whereas the Arg-370-Gln-substituted enzyme retains some residual activity, being found in a patient suffering from the milder juvenile form of the disease. Detailed analysis reveals that formation of the apparent salt bridge depends critically on the presence of aspartic acid and arginine residues at positions 335 and 370, respectively. Substitution by various other amino acids, including glutamic acid and lysine, affects enzyme function severely. Biosynthesis and immunoprecipitation studies indicate that the Asp-335-Val substitution affects folding of arylsulphatase A more severely than either the Arg-370-Trp or Arg-370-Gln substitutions. In vitro mutagenesis data show that clinical severity correlates with the space occupied by residue 370. The combination with structural data suggests that the bulky tryptophan residue broadens the cleft held together by the apparent salt bridge, whereas the smaller glutamine residue still allows the cleft to close, yielding a less severely affected enzyme. The position of residue 370 in the three-dimensional structure of the enzyme provides a plausible explanation for the differing severities in loss of enzyme function caused by the mutations and thus the clinical phenotype.

Adolescent↗

PubMed2002

Ab initio conformational studies on diols and binary diol-water systems using DFT methods. Intramolecular hydrogen bonding and 1:1 complex formation with water.

Studies on the conformational equilibrium for the following diols, ethane-1,2-diol (12EG, CAS 107-21-1), 2R-D-(-)-propane-1,2-diol (12PG, CAS 4254-14-2), (2S,3S)-L-(+)-butane-2,3-diol (L23BD, CAS 19132-06-0), and (2S,3R)-meso-butane-2,3-diol (m23BD, CAS 5341-95-7), are described using Gaussian ab initio calculations involving density functional theory (DFT) methods. We also report in this article results on the stability and conformation for the 1:1 water-diol complex formed by ethane-1,2-diol, propane-1,2-diol, and L- and meso-butane-2,3-diol. The relative stability of the intramolecular (internal) hydrogen bond in a range of diols (n = 2 to 6), based on ab initio geometry optimization and determination of the -O...H- distance, dOH, and -O-H...O- angle, theta, increases through the sequence 1,2 approximately equals 2,3 < 1,3 < 1,4 approximately equals 1,5 approximately equals 1,6, as judged from the bond linearity and -O...H- separation. Quantum mechanical and topological analysis of possible intramolecular hydrogen bonding in this complete series of diols provides convincing evidence for this in diols in which the hydroxyl groups are separated by three or more carbon atoms, that is, in (n, n+m) diols for m > or = 2, but not for ethane-1,2-diol or other vicinal diols, which do not satisfy Popelier's topological and electron density criteria based on the AIM theory of Bader. Based on these criteria it is unlikely that vicinal diols are in fact capable of forming an intramolecular hydrogen bond, in spite of geometric and spectroscopic data in the literature suggesting otherwise.

Journal Article↗