Raymond J. Abraham

The gating of nucleotide-sensitive K+ channels in insulin-secreting cells can be modulated by changes in the ratio ATP4−/ADP3− and by nonhydrolyzable derivatives of both ATP and ADP

SummaryThe31P-NMR technique has been used to assess the intracellular ratios and concentrations of mobile ATP and ADP and the intracellular pH in an insulin-secreting cell line, RINm5F. The single-channel current-recording technique has been used to investigate the effects of changes in the concentrations of ATP and ADP on the gating of nucleotide-dependent K+ channels. Adding ATP to the membrane inside closes these channels. However, in the continued presence of ATP adding ADP invariably leads to the reactivation of ATP-inhibited K+ channels, even at ATP4−/ADP3− concentration ratios greater than 7∶1. Interactions between ATP4− and ADP3− seem competitive. An increase in the concentration ratio ATP4−/ADP3− consistently evoked a decrease in the open-state probability of K+ channels; conversely a decrease in ATP4−/ADP3− increased the frequency of K+ channel opening events. Channel gating was also influenced by changes in the absolute concentrations of ATP4− and ADP3−, at constant free concentration ratios. ADP-evoked stimulation of ATP-inhibited channels did not result from phosphorylation of the channel, as ADP-β-S, a nonhydrolyzable analog of ADP, not only stimulated but enhanced ADP-induced activation of K+ channels, in the presence of ATP. Similarly, ADP was able to activate K+ channels in the presence of two nonhydrolyzable derivatives of ATP, AMP-PNP and βγmethylene ATP.

Rotational isomerism—XIII : Rotational isomerism in furfuraldehyde

Abstract The equilibrium between the cis and trans isomers of furfuraldehyde has been studied by measuring the stereospecific coupling constants between the aldehyde and ring protons in various solvents. These values when combined with the observed values of the couplings in the individual conformers at low temperatures give the energy difference between the cis and trans forms in these solvents. These values together with other previous measurements demonstrate the large solvent effect on this equilibrium. E( cis )-E( trans ) is +1·5 kcals/mole in the vapour, much smaller in non-polar solvents (+0·3 kcals/mole in CF 2 Cl 2 ), ca 0 in CHCl 3 and becomes negative in polar media (−1·0 kcals/mole in the pure liquid). This solvent dependence is given a quantitative explanation in terms of a known theory of solvation. The energy of activation of this equilibrium also shows a pronounced dependence on the medium and this is also quantitatively explained by the same theory. Finally the vapour state values of the energy difference and energy of activation agree with calculated values based on current MO theories.

A theoretical and crystallographic study of the geometries and conformations of fluoro-olefins as peptide analogues

Abstract The crystal structure of 2-cyclohexylidene-2-fluoroacetic acid ( 1 ) is reported. Geometry studies of related compounds using ab initio MO theory at the STO-3G level of approximation give structures in reasonable agreement with the structure of 1 .

The molecular structure of N-benzylidene-aniline

Abstract The molecular structure of N-benzylidene-aniline has been studied experimentally by the gas electron diffraction method, and also by molecular mechanics calculations. Both approaches gave the same results for the most stable conformer of the free molecule. The phenyl ring bonded to the carbon end of the CN bond was found to be coplanar with this bond, while the other phenyl ring was extensively (ca. 52°) rotated about the NΦ bond.

The morse curve as a non-bonded potential function

Abstract The morse curve has considerable advantages over the exp-6 and 12-6 potentials as a non-bonded potential function. The three potential functions are compared and the equivalent Morse curves of several commonly used steric potentials are given.

COSMIC(90): An improved molecular mechanics treatment of hydrocarbons and conjugated systems

SummaryFour modifications to the COSMIC molecular mechanics force field are described, which greatly increase both its versatility and the accuracy of calculated conformational energies. The Hill non-bonded van der Waals potential function has been replaced by a two-parameter Morse curve and a new H-H potential, similar to that in MM3, incorporated. Hydrocarbon energies in particular are much improved.A simple iterative Hückel pi-electron molecular orbital calculation allows modelling of conjugated systems. Calculated bond lengths and rotational barriers for a series of conjugated hydrocarbons and nitrogen heterocycles are shown to be as accurate as those determined by the MM2 SCF method.Explicit hydrogen-bonding potentials for H-bond acceptor-donor atom pairs have been included to give better hydrogen bond energies and lengths. The van der Waals radii of protonic hydrogens are reduced to 0.5 Å and the energy well depth is increased to 1.0 kcal mol-1.Two new general atom types, N+sp2 and O-sp3, have been introduced which allow a wide variety of charged conjugated systems to be studied. A minimum of parameterisation is required, as the new types are easily included in the Hückel scheme which automatically adjusts bond and torsional parameters according to the defined bond-order relationships.

A molecular mechanics calculation of conformational energies and barrier heights in haloalkanes

Abstract A molecular mechanics calculation of conformational energies and barrier heights in substituted fluoro- and chloroethanes and -propanes is given which reproduces reasonably well all the available experimental data on these compounds. This was achieved by the use of non-bonded potential functions for chlorine and fluorine very different from those previously used.

The proton magnetic resonance spectra of porphyrins—VII: Synthesis and NMR studies of thallium(III) coproporphyrin chelates

Abstract The four coproporphyrin “type-isomers” have been synthesized as their tetramethyl esters ( 1 ) through modifications of existing procedures. When treated with thallium(III) trifluoroacetate, these porphyrins furnish the corresponding aquo porphinatothallium(III) hydroxides ( 2 ) after ligand exchange induced by chromatography on deactivated alumina. The proton NMR spectra of the chloroform solutions of thallium(III) coproporphyrins show a pronounced concentration dependence, all resonances moving to low field upon dilution; the spectra of the type-III and -IV isomers show additional fine structure in solution. Both the meso - and β-Me protons show thallium-proton spin couplings. These results are interpreted in terms of a monomer-dimer equilibrium. In the dimers of the type-I and -II chelates, the rings lie directly one above another, whereas with the type-III and -IV complexes, steric repulsions of the propionate side-chains cause lateral displacement of one molecule in the dimer relative to the other, resulting in the observed fine structure in the spectra. The inter-porphyrin distances and lateral displacements are calculated on this basis and are compared with the corresponding dimers of the parent coproporphyrins, with which there are considerable similarities.

Conformational analysis. Part 28. OH⋯F hydrogen bonding and the conformation of trans-2-fluorocyclohexanol

The 1H and 13C NMR spectra of trans-2-fluorocyclohexanol 1 and the methyl ether 2 have been obtained in a variety of solvents and temperatures. From the low-temperature spectra the proportions of the ax–ax and eq–eq conformers were obtained by direct integration together with the vicinal HH couplings of the 2-proton in the dominant eq–eq conformer. From these results the conformer populations and energies in a variety of solvents are given.In 1 ΔG(aa–ee) varies from 1.5 kcal mol–1(1 cal = 4.184 J) in non polar solvents (e.g. CCl4) to ca. 1.2 kcal mol–1 in very polar solvents (acetone), whereas in 2 the corresponding values are 0.4 and 1.0 kcal mol–1. The proton donor solvents CDCl3 and CD2Cl2 are exceptions due to preferential CH⋯O hydrogen bonding in the eq–eq form.These figures are explained by solvation theory, which also provides the vapour state free energy differences of 1.6 kcal mol–1 1 and 0.1 kcal mol–1 2. In 1 ΔS is zero and ΔH equals ΔG but in 2 values of ΔS of 2.0 cal mol–1 K–1 and of ΔH of 1.1 kcal mol–1 in non polar media and 0.7 kcal mol–1 for the vapour are obtained. These values may be compared with those calculated by ab initio theory at the 6-31G*(MP2) level of 1.1 kcal mol–1 1 and –0.75 kcal mol–1 2. In both cases the eq–eq conformer is more stable than predicted, by 0.5 and 1.5 kcal mol–1.Comparison of the conformer energies with those obtained from the ΔG values for the monosubstituted cyclohexanes gives the OH⋯F hydrogen bonding attraction in the eq–eq conformer as 1.6 kcal mol–1 whilst the gauche OMe⋯F interaction is neutral, neither repulsive nor attractive. These figures support previous theoretical interpretations that the gauche form of 2-fluoroethanol is predominant due to OH⋯F hydrogen bonding and show also that the previous discrepancy between experimental measurements in the condensed phase and theory is due to solvation.

Rotational isomerism—XXI: The conformation of 2-amino-3-fluoropropanoic acid (2-afp) and 2-fluoro-3-aminopropanoic acid (3-afp) as the zwitterion, cation and anion, an nmr and mo study

Abstract The NMR spectra of 2-AFP And 3-AFP in neutral, acid and alkaline solutions have been obtained and completely analysed to give the 1 H, 19 F and the 13 C chemical shifts and the HH, HF and CF coupling constants. In the analysis the use of FT spectra with inversion recovery sequences enabled an unambiguous assignment of the complex proton region to be made in certain cases due to the different relaxation times of the protons. The rotamer populations and hence relative energies have been obtained from the 3 J HH couplings, using calculated rotamer couplings which explicitly include the orientation dependence of electronegative substituents. A MO investigation of the rotamer energies of the zwitterions, anions and cations is given. The inclusion of the counterion into the CNDO wave function gives calculated rotamer energies in complete agreement with those observed for 2-AFP. In 3-AFP, the counter-ion method cannot fully compensate for the larger interactions between the charged groups. Calculations on related molecules including β-alanine show this is a general effect, possibly due to the solvated water molecules.