Ladislaus L. Torday

Vitamin E models. Shortened sidechain models of α, β, γ and δ tocopherol and tocotrienol: a density functional study

Model compounds of α-, β-, γ-, and δ-tocopherol and Tocotrienol, as well as their sulphur and selenium congeners, were subjected to density functional analysis. The mono methyl substitution either stabilized or destabilized the ring structures to a small extent as assessed in terms of isodesmic reactions. In general, multiple methyl substitutions destabilized the ring. Dimethyl para-substitution results in electronic stabilization and steric repulsion being nearly additive. This was not the case for ortho-dimethyl derivatives, whereby steric repulsions dominate; the meta-substituted models reflect the same trend to a lesser degree. Structurally, the phenolic hydroxyl orientation was approximately planar, with the hydroxyl proton oriented away from the adjacent Me group whenever the structure permitted such an orientation.

Vitamin E models. Can the anti-oxidant and pro-oxidant dichotomy of α-tocopherol be related to ionic ring closing and radical ring opening redox reactions?

Abstract The free radical scavenging mechanism, leading to a quinodal structure via an oxidative ring opening is exothermic. However, the ionic oxidative ring opening is endothermic. Consequently, the ionic reductive ring closing must be exothermic. This leads to the suggestion that Vitamin E may be recovered, unchanged, thus effectively acts as a catalyst for the following reaction 2 HOO + H 3 O (+) + NADH →2 HOOH + H 2 O + NAD (+) , Δ E≈−120 kcal mol −1 . As Vitamin E is biologically recycled, a single α-tocopherol molecule may convert numerous HOO radical to H2O2 which is accumulated if not removed at the same rate, enzymatically, with the participation of catalase (Fe) or glutathione peroxidase, GPx(Se). This accumulation of peroxide, which may be referred to as a ‘peroxide traffic jam’, may well be the reason of the pro-oxidant effect of Vitamin E.

Conformational effects of one glycine residue on the other glycine residues in the Ac-Gly-Gly-Gly-NHMe tripeptide motif: an ab initio exploratory study

Abstract Ab initio molecular computations were carried out on the tripeptide model, Ac-Gly-Gly-Gly-NHMe at the RHF/3-21G ab initio level of theory. Two of the glycine residues were chosen at a time to be in the fully extended, or β (C 5 ) conformation, in order to monitor the effects on the third residue with varying the backbone conformation. The topologies of each of the three Ramachandran type conformational potential energy surfaces were analyzed and five minima (β, γ l , γ d , δ l , δ d ) associated with each one of the three glycine residues, were located for each surface.

Density functional molecular computations on protonated serotonin in the gas phase and various solvent media

Abstract 5-Hydroxytryptamine (serotonin) was geometry optimized at the B3YP/6-31G(d) level of theory to determine the energetically most favourable conformations of the aromatic hydroxyl group and the protonated ethylamine side chain. The hydroxyl group was found to be most stable at anti for all conformations, and the two lowest energy gas phase conformers found were: χ 2 = g + , χ 3 = g − and χ 2 = g − , χ 3 = g + . The protonated amino group was found equally stable at g + , g − and anti . The transition structures linking each gas phase minimum were also computed. Minima found were subjected to solvation calculations in chloroform, DMSO, ethanol and water, which shifted their relative stabilities.

Conformational potential energy surfaces of a lycopene model

Abstract Ab initio conformational analysis has been carried out at the RHF/3-21G level of theory. Computations were performed on a tail-end lycopene (Model B). Both the all-trans and the 5-cis-isomers were studied. The fully planar structure turned out to be a second-order saddle point, which indicated that lycopene itself is not planar. Most of the conformers of the 5-cis-isomer are more stable than the corresponding conformers of the all-trans-isomer. This stability is in agreement with the observation that even though lycopene is biosynthesized in plants as the all-trans form, in the human body over 65% exists in one of the cis-forms and less than 35% remains in its all-trans form.

How reliable could economic Hartree–Fock computations be in studying large, folded peptides? A comparative HF and DFT case study on N- and C-protected aspartic acid

Abstract In this study, potential energy hypersurfaces have been generated and analyzed for each of the nine possible backbone (BB) conformations for both the endo and exo forms of N-acetyl- l -aspartic acid N′-methylamide. Ab initio calculations were carried out at RHF/3-21G, RHF/6-31G(d), and B3LYP/6-31G(d) levels for all backbone conformations. The relative energies, as well as stabilization energies exerted by the sidechain (SC) on the backbone, were calculated for all stable conformers. All sidechain–sidechain (HO⋯OC), backbone–backbone (N–H⋯OC), and sidechain–backbone (N–H⋯OC; N–H⋯OH) hydrogen bond interactions were analyzed. The appearance of the traditionally absent αL and eL conformers may be recognized as special geometric orientation which the aspartyl residue manifests during peptide folding or ligand docking in a receptor that contains aspartic acids in its ligand recognition sites. At all three levels of theory, there exists a trend between the hydrogen bond distance and ring size. In addition, strikingly high correlations between the torsional angles (R2=0.9937 for RHF/6-31G(d) versus RHF/3-21G; R2=0.9967 for B3LYP/6-31G(d) versus RHF/6-31G(d); R2=0.9914 for B3LYP/6-31G(d) versus RHF/3-21G) and between the ΔE values in kcal/mol (R2=0.9424 for RHF/6-31G(d) versus RHF/3-21G; R2=0.9108 for B3LYP/6-31G(d) versus RHF/6-31G(d); R2=0.9434 B3LYP/6-31G(d) versus RHF/3-21G) found at the different ab initio levels suggest that calculations carried out at the lower levels (i.e. at RHF/3-21G) are still significant.

Improvement by phosphoramidon of damaged endothelial function in porcine coronary artery.

BACKGROUND The bradykinin (BK)-induced endothelium-dependent relaxation is impaired in the presence of elevated potassium concentration enhancing the vasospastic tendency of large coronary arteries. Inhibition of the angiotensin-converting enzyme responsible for bradykinin degradation was found to enhance the endothelium-dependent relaxation by BK. The aim of the present study was to investigate the effect of phosphoramidon, known to inhibit a BK-metabolizing neutral endopeptidase enzyme, on relaxation of porcine-isolated coronary artery in depolarizing solution. METHODS Endothelium intact porcine coronary artery rings were studied in organ chambers. The rings were isometrically contracted with potassium chloride (30 mmol/L) and the response to BK (1 to 1,000 nmol/L)-induced relaxation was investigated in the presence of nitric oxide synthase inhibitor Nomega-nitro-L-arginine (300 micromol/L) alone and in combination with the cyclooxygenase inhibitor indomethacin (10 micromol/L), and that of the inhibitor of calcium-dependent potassium channels tetraethylammonium (7 mmol/L). Under these conditions, phosphoramidon (10 micromol/L), an inhibitor of a neutral endopeptidase enzyme (EC.3.4.24.11.), which is responsible for the degradation of BK, was used to enhance the endothelium-dependent relaxation. RESULTS Phosphoramidon potentiated the maximum vasorelaxant effect of BK in Nomega-nitro-L-arginine (control 26.6%+/-10.86% versus phosphoramidon 49.05%+/-4.52%; n = 6, p < 0.05) or in Nomega-nitro-L-arginine + indomethacin-pretreated rings (control 20.7%+/-9.92% versus phosphoramidon 42.0%+/-12.26%; n = 5, p < 0.05) and this increased vasodilation was not modified by tetraethylammonium. CONCLUSIONS In the present study phosphoramidon potentiated the effect of BK in the absence of nitric oxide and prostaglandins in porcine-isolated coronary artery. This effect did not depend on tetraethylammonium-sensitive potassium channels. Phosphoramidon may be a useful pharmacologic tool for preserving the vasorelaxing capacity of coronary arteries after cardioplegia.

An ab initio and DFT conformational analysis of unsubstituted and ω-substituted ethyl-benzene: (Ph-CH2-CH2-Z; Z = -H, -F, -NH3+, -CH3)

Abstract A series of compounds of Ph–CH 2 –CH 2 –Z, with substituents Z=–H, –F, –NH 3 + , and –CH 3 , were subjected to conformational analysis. Conformational potential energy surfaces were generated and their minima were geometrically optimized at three levels of theory. The relative stabilities of the minima correlated with the electron withdrawing nature of the substituents (Z).

Conformational dependence of the intrinsic acidity of the aspartic acid residue sidechain in N-acetyl-l-aspartic acid-N′-methylamide

Abstract The sidechain conformational potential energy hypersurfaces (PEHS) for the γL, βL, αL, and αD backbone conformations of N-acetyl- l -aspartate-N′-methylamide were generated. Of the 81 possible conformers initially expected for the aspartate residue, only seven were found after geometric optimizations at the B3LYP/6-31G(d) level of theory. No stable conformers could be located in the δL, eL, γD, δD, and eD backbone conformations. The ‘adiabatic’ deprotonation energies for the endo and exo forms of N-acetyl- l -aspartic acid-N′-methylamide were calculated by comparing their optimized relative energies against those found for the seven stable conformers of N-acetyl- l -aspartate-N′-methylamide. Sidechain conformational PEHSs were also generated for the estimation of ‘vertical’ deprotonation energies for both endo and exo forms of N-acetyl- l -aspartic acid-N′-methylamide. All backbone–sidechain (N–H⋯−O–C) and backbone–backbone (N–H⋯OC) hydrogen bond interactions were analyzed. A total of two backbone–backbone and four backbone–sidechain interactions were found for N-acetyl- l -aspartate-N′-methylamide. The deprotonated sidechain of N-acetyl- l -aspartate-N′-methylamide may allow the aspartyl residue to form strong hydrogen bond interactions (since it is negatively charged) which may be significant in such processes as protein–ligand recognition and ligand binding. As a primary example, the molecular geometry of the aspartyl residue may be important in peptide folding, such as that in the RGD tripeptide.

Molecular computations on lipids: A numbering system for phospholipids and triglyceride

A standardized numbering system is elaborated upon for the efficient generation of input data for molecular computations on phospholipids and triglycerides. The advantages of such a comprehensive system in terms of the extraction of structural data and the increase in throughput allowing for the identification of the complete set of stable conformers are discussed.