Comment on "about the calculation of exchange coupling constants using density-functional theory: the role of the self-interaction error" [J. Chem. Phys. 123, 164110 (2005)].
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Comment↗
Biomedical subjects
V Barone
Publications and source records attributed to V Barone.
Nucleophilic cyclopropane ring opening in duocarmycin SA derivatives by methanol under acid conditions: a quantum mechanical study in the gas-phase and in solution.
We present a quantum-mechanical study of the S(N)2 acid-catalyzed solvolysis with methanol of seven simplified duocarmycin SA (DNA alkylating agent) derivatives characterized by spirocyclic systems of increasing complexity, all containing the cyclopropyl/cyclohexadienone substrate. The reaction has been studied at the DFT-PBE0/6-31G(d) level in the gas phase and in methanol solution, using in the latter case the polarizable continuum model (PCM) to describe solvent effects. The results delivered by this computational protocol are in full agreement with the available experimental evidences and are not modified by extension of the basis set or by using a second-order many-body treatment (MP2) in place of DFT. This allows investigation of substituent effects in terms of structure/reactivity relationships and evaluation of the role of stereoelectronic effects. Furthermore, reactivity indices (hardness, electrophilicity) have been computed and shown to correlate well with activation energies. Together with their intrinsic interest, the details of the mechanism of the acid-catalyzed nucleophilic addition to the activated cyclopropane issuing from the present study pave the route for a deeper understanding of the molecular basis for the remarkable profile of the DNA-alkylation by DSA derivatives.
Antibiotics, Antineoplastic↗
A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood.
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Adult↗
Homer proteins and InsP(3) receptors co-localise in the longitudinal sarcoplasmic reticulum of skeletal muscle fibres.
Striated muscle represents one of the best models for studies on Ca(2+) signalling. However, although much is known on the localisation and molecular interactions of the ryanodine receptors (RyRs), far less is known on the localisation and on the molecular interactions of the inositol trisphosphate receptors (InsP(3)Rs) in striated muscle cells. Recently, members of the Homer protein family have been shown to cluster type 1 metabotropic glutamate receptors (mGluR1) in the plasma membrane and to interact with InsP(3)R in the endoplasmic reticulum of neurons. Thus, these scaffolding proteins are good candidates for organising plasma membrane receptors and intracellular effector proteins in signalosomes involved in intracellular Ca(2+) signalling. Homer proteins are also expressed in skeletal muscle, and the type 1 ryanodine receptor (RyR1) contains a specific Homer-binding motif. We report here on the relative sub-cellular localisation of InsP(3)Rs and Homer proteins in skeletal muscle cells with respect to the localisation of RyRs. Immunofluorescence analysis showed that both Homer and InsP(3)R proteins present a staining pattern indicative of a localisation at the Z-line, clearly distinct from that of RyR1. Consistent herewith, in sub-cellular fractionation experiments, Homer proteins and InsP(3)R were both found in the fractions enriched in longitudinal sarcoplasmic reticulum (LSR) but not in fractions of terminal cisternae that are enriched in RyRs. Thus, in skeletal muscle, Homer proteins may play a role in the organisation of a second Ca(2+) signalling compartment containing the InsP(3)R, but are apparently not involved in the organisation of RyRs at triads.
Antibodies↗
Understanding the role of stereoelectronic effects in determining collagen stability. 1. A quantum mechanical study of proline, hydroxyproline, and fluoroproline dipeptide analogues in aqueous solution.
The importance of local (intraresidue) effects in determining the stability of the collagen triple helix has been investigated with special reference to the role played by hydroxyproline. To this end the dipeptide analogues of L-proline (ProDA), 4(R)-hydroxy-L-proline (HypDA), and 4(R)-fluoro-L-proline (FlpDA) have been studied by means of quantum mechanical ab initio calculations, taking into account solvent effects by the polarizable continuum model (PCM). Our results confirm that the relative stability of up puckerings of the pyrrolidine ring increases with the electronegativity of the 4(R) substituent (X), whereas down puckerings are favored by 4(S) electronegative substituents. Calculations on model compounds show that this effect is due to the interaction between vicinal C-H bonding and C-X antibonding orbitals. Electronegative substituents on the pyrrolidine ring affect cis-trans isomerism around the peptidic bond, with trans isomers stabilized by 4(R) substituents and cis isomers by 4(S) substituents. Also the hydrogen bonding power of the carbonyl moiety following the pyrrolidine ring is affected by 4(R) substituents, but this effect is tuned by the polarity of the embedding medium. Finally, up puckering favors smaller values of the backbone dihedrals phi and psi. All these results strongly support the proposal that the stability of triple helices containing fluorinated or hydroxylated prolines in Y positions is related to the necessity of having up puckerings in those positions.
Collagen↗
Electron transfer in the [Pt(NH3)4]2+ [W(CN)8]3- donor-acceptor system. The environment effect: a time-dependent density functional study.
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Journal Article↗
Through-bond and through-space J(FF) spin-spin coupling in peridifluoronaphthalenes: accurate DFT evaluation of the four contributions.
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Fluorine↗
Interplay of intrinsic and environmental effects on the magnetic properties of free radicals issuing from H-atom addition to cytosine.
Possible radical reaction products issuing from H-atom addition to cytosine have been characterized and analyzed by means of a comprehensive quantum mechanical approach including density functional computations (B3LYP), together with simulation of the solvent by the polarizable continuum model (PCM), and averaging of spectroscopic properties over the most important vibrational motions. The hyperfine couplings of the semirigid 5,6-dihydrocytos-6yl radical computed at the optimized geometry are in good agreement with their experimental counterparts. On the other hand, vibrational averaging is mandatory for obtaining an effectively planar structure for the 5,6-dihydrocytos-5yl radical with the consequent equivalence of beta-hydrogens. Finally, only proper consideration of environmental effects restores the agreement between computed and experimental couplings for the base anion protonated at N3.
Cytosine↗
Structure and conformational behavior of biopolymers by density functional calculations employing periodic boundary conditions. I. The case of polyglycine, polyalanine, and poly-alpha-aminoisobutyric acid in vacuo.
Fully quantum mechanical calculations exploiting periodic boundary conditions (PBC) have been applied to the study of four different regular structures (alpha- and 3(10)-helix, fully extended and repeated gamma-turns) of the infinite polypeptides of glycine, alanine, and alpha-aminoisobutyric acid (Aib) in vacuo. alpha-Helix is predicted to be the most stable conformer for polyalanine and polyglycine, being stabilized over the 3(10)-helix mainly by more favorable dipole-dipole interactions. Contrary to previous suggestions, steric effects and hydrogen-bond strengths are comparable for both helix structures. 3(10)-Helix is preferred for poly-Aib, since in this case alpha-helix is strongly distorted due to unfavorable intrachain repulsions. Extended structures and repeated gamma-turns are much less stable than helix structures for all of the polypeptides examined, mainly due to the absence of favorable long-range interactions. The optimized geometries are in good agreement with the available experimental data and reveal a remarkable dependence on the nature of the residue forming the polypeptides; at the same time the electronic and structural parameters of each residue strongly depend on the secondary structure of the polypeptides.
Aminoisobutyric Acids↗
Intramolecular C-H--O interaction between lactam oxygen and N-alkyl protons.
We report evidence of an unusual C-H--O interaction between an alpha-methylene hydrogen of the alkylamine chain of substituted (N,N-dimethylamino)propyl-azetidinones, substituted (N,N-dimethylamino)propyl-thiazolidinones and substituted (N,N-dimethylamino)propyl-thiazinone and the lactam carbonyl oxygen. NMR analysis results, supported by molecular mechanic predictions, were in agreement with ab initio calculations. The observed interaction shorting the nitrogen-nitrogen distance in the H1-histamine antagonist, 2-(4-methylphenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-one (1) could explain its fitting with the H1-antihistaminic pharmacophoric model and the high antihistaminic activity.
Alkylation↗
The gas 5 gene shows four alternative splicing patterns without coding for a protein.
The murine gas5 gene was originally isolated based on its preferential expression in the growth arrest phase of the cell cycle. This gene contains 12 exons from which two alternatively spliced transcripts have been initially identified. More recently, it has been reported that both human and murine gas5 genes contain in their introns sequences homologous to the small nucleolar RNAs involved in the processing of ribosomal RNA. Here we report on the identification and analysis of the expression pattern of two novel alternatively spliced mouse gas5 mRNAs which contain no obvious open reading frame (ORF). Using antibodies generated against the putative amino acid sequence deduced from the gas5 cDNAs, we were not able to detect any Gas5 protein in cultured cells or murine tissues extracts. Even more definitive evidence that the gas5 gene may not encode a protein was obtained by cloning and sequencing the rat gas5 gene which revealed that the putative ORF is interrupted by a stop codon after the first 13 amino acids.
3T3 Cells↗
Intracellular Ca(2+) release channels in evolution.
Intracellular Ca(2+)-release channels (ICRCs) form a superfamily of genes that encompasses two distinct subfamilies: the inositol trisphosphate receptor and the ryanodine receptor genes, which encode the largest ion channels known today. During evolution from nematodes to man, mechanisms of gene duplication and divergence have increased the number of known ICRC genes, which have been gradually co-opted to contribute to the increasing complexity of intracellular Ca(2+) signalling required for regulation of specialised eukaryotic cell activities.
Alternative Splicing↗
Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning.
Deletion of the ryanodine receptor type 3 (RyR3) results in specific changes in hippocampal synaptic plasticity, without affecting hippocampal morphology, basal synaptic transmission or presynaptic function. Robust long-term potentiation (LTP) induced by repeated, strong tetanization in the CA1 region and in the dentate gyrus was unaltered in hippocampal slices in vitro, whereas weak forms of plasticity generated by either a single weak tetanization or depotentiation of a robust LTP were impaired. These distinct physiological deficits were paralleled by a reduced flexibility in re-learning a new target in the water-maze. In contrast, learning performance in the acquisition phase and during probe trial did not differ between the mutants and their wild-type littermates. In the open-field, RyR3(-/-) mice displayed a normal exploration and habituation, but had an increased speed of locomotion and a mild tendency to circular running. The observed physiological and behavioral effects implicate RyR3-mediated Ca(2+) release in the intracellular processes underlying spatial learning and hippocampal synaptic plasticity.
Animals↗
Contribution of ryanodine receptor type 3 to Ca(2+) sparks in embryonic mouse skeletal muscle.
The kinetic behavior of Ca(2+) sparks in knockout mice lacking a specific ryanodine receptor (RyR) isoform should provide molecular information on function and assembly of clusters of RyRs. We examined resting Ca(2+) sparks in RyR type 3-null intercostal myotubes from embryonic day 18 (E18) mice and compared them to Ca(2+) sparks in wild-type (wt) mice of the same age and to Ca(2+) sparks in fast-twitch muscle cells from the foot of wt adult mice. Sparks from RyR type 3-null embryonic cells (368 events) were significantly smaller, briefer, and had a faster time to peak than sparks from wt cells (280 events) of the same age. Sparks in adult cells (220 events) were infrequent, yet they were highly reproducible with population means smaller than those in embryonic RyR type 3-null cells but similar to those reported in adult amphibian skeletal muscle fibers. Three-dimensional representations of the spark peak intensity (DeltaF/Fo) vs. full width at half-maximal intensity (FWHM) vs. full duration at half-maximal intensity (FTHM) showed that wt embryonic sparks were considerably more variable in size and kinetics than sparks in adult muscle. In all cases, tetracaine (0.2 mM) abolished Ca(2+) spark activity, whereas caffeine (0.1 mM) lengthened the spark duration in wt embryonic and adult cells but not in RyR type 3-null cells. These results confirmed that sparks arose from RyRs. The low caffeine sensitivity of RyR type 3-null cells is entirely consistent with observations by other investigators. There are three conclusions from this study: i) RyR type-1 engages in Ca(2+) spark activity in the absence of other RyR isoforms in RyR type 3-null myotubes; ii) Ca(2+) sparks with parameters similar to those reported in adult amphibian skeletal muscle can be detected, albeit at a low frequency, in adult mammalian skeletal muscle cells; and iii) a major contributor to the unusually large Ca(2+) sparks observed in normal (wt) embryonic muscle is RyR type 3. To explain the reduction in the size of sparks in adult compared to embryonic skeletal muscle, we suggest that in embryonic muscle, RyR type 1 and RyR type 3 channels co-contribute to Ca(2+) release during the same spark and that Ca(2+) sparks undergo a maturation process which involves a decrease in RyR type 3.
Animals↗
Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families.
Point mutations in the ryanodine receptor (RYR1) gene are associated with malignant hyperthermia, an autosomal dominant disorder triggered in susceptible people (MHS) by volatile anaesthetics and depolarising skeletal muscle relaxants. To date, 17 missense point mutations have been identified in the human RYR1 gene by screening of the cDNA obtained from muscle biopsies. Here we report single strand conformation polymorphism (SSCP) screening for nine of the most frequent RYR1 mutations using genomic DNA isolated from MHS patients. In addition, the Argl63Cys mutation was analysed by restriction enzyme digestion. We analysed 57 unrelated patients and detected seven of the known RYR1 point mutations. Furthermore, we found a new mutation, Arg2454His, segregating with the MHS phenotype in a large pedigree and a novel amino acid substitution at position 2436 in another patient, indicating a 15.8% frequency of these mutations in Italian patients. A new polymorphic site in intron 16 that causes the substitution of a G at position -7 with a C residue was identified.
Caffeine↗
Voltage-controlled Ca2+ release in normal and ryanodine receptor type 3 (RyR3)-deficient mouse myotubes.
1. Primary cultured myotubes were derived from satellite cells of the diaphragm obtained from both normal mice (RyR3+/+) and mice with a targeted mutation eliminating expression of the type 3 isoform of the ryanodine receptor (RyR3-/-). Using the whole-cell patch clamp technique, L-type Ca2+ currents were measured during step depolarizations. Simultaneously, intracellular Ca2+ transients were recorded with the fluorescent indicator dye fura-2. 2. After correction for non-instantaneous binding of Ca2+ to the indicator dye and taking into account the dynamics of Ca2+ binding to intracellular constituents, an estimate of the time course of the Ca2+ release rate from the sarcoplasmic reticulum (SR) was obtained. 3. The calculated SR Ca2+ release flux exhibited a marked peak within less than 12 ms after the onset of the voltage-clamp depolarization and fell rapidly thereafter to a five times lower, almost steady level. It declined rapidly after termination of the depolarization. 4. Signals in normal and RyR3-deficient myotubes showed no significant difference in the activation of Ca2+ conductance and in amplitude, time course and voltage dependence of the Ca2+ efflux from the SR. 5. In conclusion, the characteristics of voltage-controlled Ca2+ release reported here are similar to those of mature mammalian muscle fibres. In contrast to differences observed in the contractile properties of RyR3-deficient muscle fibres, a contribution of RyR3 to excitation-contraction coupling could not be detected in myotubes.
Algorithms↗
Structure and mutation analysis of the glycogen storage disease type 1b gene.
Glycogen storage disease (GSD) 1b is the deficiency of endoplasmic reticulum glucose-6-phosphate (G6P) transport. We here report the structure of the gene encoding a protein likely to be responsible for G6P transport, and its mapping to human chromosome 11q23.3. The gene is composed of nine exons spanning a genomic region of approximately 4 kb. Primers based on the genomic sequence were used in single strand conformation polymorphism (SSCP) analysis and mutations were found in six out of seven GSD 1b patients analysed.
Antiporters↗
Contractile impairment and structural alterations of skeletal muscles from knockout mice lacking type 1 and type 3 ryanodine receptors.
Skeletal muscle contraction is triggered by the release of Ca2+ from the sarcoplasmic reticulum through the type 1 ryanodine receptor (RyR1). Recently it has been shown that also the type 3 isoform of ryanodine receptor (RyR3), which is expressed in some mammalian skeletal muscles, may participate in the regulation of skeletal muscle contraction. Here we report the generation and the characterization of double mutant mice carrying a targeted disruption of both the RyR1 and the RyR3 genes (RyR1-/-;RyR3-/-). Skeletal muscles from mice homozygous for both mutations are unable to contract in response to caffeine and to ryanodine. In addition, they show a very poor capability to develop tension when directly activated with micromolar [Ca2+]i after membrane permeabilization which indicates either poor development or degeneration of the myofibrils. This was confirmed by biochemical analysis of contractile proteins. Electron microscopy confirms small size of myofibrils and shows complete absence of feet (RyRs) in the junctional SR.
Animals↗