Thermodynamic role of glutathione oxidation by peroxide and peroxybicarbonate in the prevention of Alzheimer's disease and cancer.

First principle quantum molecular computations have been carried out at the B3LYP/6-31G(d,p) and G3MP2B3 levels of theory on ethyl mercaptan and diethyl disulfide to study their full conformational space. The consequences of molecular axis chirality for the potential energy hypersurface of diethyl disulfide was fully explored. Thermodynamic functions (U, H, S, and G) have been computed for every conformer of the products as well as the reactants of the redox systems studied. Relative values of the thermodynamic functions were calculated with respect to the reference structures with anti orientation. The energetics of the following Red-Ox reactions Et-SH+HO-OH+HS-Et --> 2H2O+Et-S-S-Et Et-SH+HO-OCOO(-)+HS-Et --> H2O+Et-S-S-Et+HCO3- have been chosen to mimic the biologically important Red-Ox reactions of glutathione G-SH+H2O2+HS-G --> 2H2O+G-S-S-G G-SH+HCO4-+HS-G --> H2O+G-S-S-G+HCO3-. The Red-Ox reaction of Et-SH --> Et-S-S-Et was found to be exothermic by first principle molecular computations and the intramolecular interactions, such as the unusual C-H...H-C noncovalent bondings were studied by Bader's atoms in molecules analysis of the electron density topology. The present paper focuses attention on the thermodynamic aspect of the redox reaction of glutathione. It has been noted previously that on going from a cancerous to a healthy cell, the entropy change is negative, corresponding to information accumulation. Likewise, the dissociation of peptide parallel beta-sheets, that dominate the plaques in Alzheimer's Disease, governs negative entropy change. It may be interesting to note, according to the results obtained in the present paper, a negative entropy change, corresponding to information accumulation.

Thermodynamic functions of molecular conformations of (2-fluoro-2-phenyl-1-ethyl)ammonium ion and (2-hydroxy-2-phenyl-1-ethyl)ammonium ion as models for protonated noradrenaline and adrenaline: first-principles computational study of conformations and thermodynamic functions for the noradrenaline and adrenaline models.

This paper reports the structural and thermodynamic consequences of substitution of the OH group by the isoelectronic F-atom in the case of the adrenaline family of molecules. The conformational landscapes were explored for the two enantiomeric forms of N-protonated-beta-fluoro-beta-phenyl-ethylamine, also called (2-fluoro-2-phenyl-1-ethyl)-ammonium ion (Model 1) and that of N-protonated-beta-hydroxy-beta-phenyl-ethylamine, also referred to as (2-hydroxy-2-phenyl-1-ethyl)-ammonium (Model 2) models of noradrenaline and adrenaline molecules. These full conformational studies were carried out by first principles of quantum mechanical computations at the B3LYP/6-31G(d,p) and G3MP2B3 levels of theory, using the Gaussian03 program. Also, frequency calculations of the stable structures were performed at the B3LYP/6-31G(d,p), and G3MP2B3 levels of theory. The thermodynamic functions (U, H, S, and G) of the various stable conformations of the title compounds were calculated at these levels of theory for the R and S stereoisomers. Relative values of the thermodynamic functions have been calculated with respect of the chosen reference conformers in which all relevant dihedral angles assumed anti orientation for the Model 1 and Model 2. Through the combination of both point and axis chirality, the enantiomeric and diastereomeric relationships of the six structures for each molecule investigated were established. Intramolecular hydrogen bonding interactions have been studied by the atoms in molecules (AIM) analysis of the electron density. The aromaticity of phenyl group has been determined by a selective hydrogenation protocol. The pattern of the extent of aromacity, due intramolecular interactions, varies very little between the two models studied.

Flexibility of "polyunsaturated fatty acid chains" and peptide backbones: A comparative ab initio study.

The conformational properties of omega-3 type of polyunsaturated fatty acid (PUFA) chains and their fragments were studied using Hartree-Fock (RHF/3-21G) and DFT (B3LYP/6-31G(d)) methods. Comparisons between a unit (U) fragment of the PUFA chain and a mono N-Ac-glycine-NHMe residue show that both structures have the same sequence of sp2-sp3-sp2 atoms. The flexibility of PUFA originates in the internal rotation about the above pairs of sigma bonds. Therefore, potential energy surfaces (PESs) were generated by a scan around the terminal dihedral angles (phi t1 and phi t2) as well as the phi 1 and psi 1 dihedrals of both 1U congeners (Me-CHCH-CH2-CHCHMe and MeCONH-CH2-CONHMe) at the RHF/3-21G level of theory. An interesting similarity was found in the flexibility between the cis allylic structure and the trans peptide models. A flat landscape can be seen in the cis 1U (hepta-2,5-diene) surface, implying that several conformations are expected to be found in this (PES). An exhaustive search carried out on the 1U and 2U models revealed that straight chain structures such as trans and cis beta (phi 1 approximately psi 1 approximately 120 degrees; phi 2 approximately psi 2 approximately -120 degrees) or trans and cis extended (phi 1 approximately psi 1 approximately phi 2 approximately psi 2 approximately 120 degrees) can be formed at the lowest energy of both isomers. However, forming helical structures, such as trans helix (phi 1 approximately -120 degrees, psi 1 approximately 12 degrees; phi 2 approximately -120 degrees, psi 2 approximately 12 degrees) or cis helix (phi 1 approximately -130 degrees, psi 1 approximately 90 degrees; phi 2 approximately -145 degrees, psi 2 approximately 90 degrees) will require more energy. These six conformations, found in 2U, were selected to construct longer chains such as 3U, 4U, 5U, and 6U to obtain the thermochemistry of secondary structures. The variation in the extension or compression of the chain length turned out to be a factor of 2 between the helical and nonhelical structures. The inside diameter of the "tube" of cis helix turned out to be 3.5 A after discounting the internal H atoms. Thermodynamic functions were computed at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d). The cis-trans isomerization energy of 1.7 +/- 0.2 kcal mol(-1) unit(-1) for all structure pairs indicates that the conformer selection was consistent. A folding energy of 0.5 +/- 0.1 kcal mol(-1) unit(-1) has been extracted from the energy comparison of the helices and most extended nonhelical structures. The entropy change associated with the folding (Delta S(folding)) is decreases faster with the degree of polymerization (n) for the cis than for the trans isomer. As a consequence, the linear relationships between (Delta G(folding)) and n for the cis and trans isomer crossed at about n = 3. This suggested that the naturally occurring cis isomer less ready to fold than the trans isomer since a greater degree of organization is exhibited by the cis isomer during the folding process. The result of this work leads to the question within the group additivity rule: could the method applied in our study of the folding of polyallylic hydrocarbons be useful in investigating the thermochemistry of protein folding?

First principle computational study on the full conformational space of L-proline diamides.

Ab initio molecular orbital computations were carried out at three levels of theory: RHF/3-21G, RHF/6-31G(d), and B3LYP/6-31G(d), on four model systems of the amino acid proline, HCO-Pro-NH2 [I], HCO-Pro-NH-Me [II], MeCO-Pro-NH2 [III], and MeCO-Pro-NH-Me [IV], representing a systematic variation in the protecting N- and C-terminal groups. Three previously located backbone conformations, gammaL, epsilonL, and alphaL, were characterized together with two ring-puckered forms syn (gauche+ = g+) or "DOWN" and anti (gauche- = g-) or "UP", as well as trans-trans, trans-cis, cis-trans, and cis-cis peptide bond isomers. The topologies of the conformational potential energy cross-sections (PECS) of the potential energy hypersurfaces (PEHS) for compounds [I]-[IV] were explored and analyzed in terms of potential energy curves (PEC), and HCO-Pro-NH2 [I] was also analyzed in terms of potential energy surfaces (PESs). Thermodynamic functions were also calculated for HCO-Pro-NH2 [I] at the CBS-4M and G3MP2 levels of theory. The study confirms that the use of the simplest model, compound [I] with P(N) = P(C) = H, along with the RHF/3-21G level of theory, is an acceptable practice for the analysis of peptide models because only minor differences in geometry and stability are observed.

Characterization of the conformational probability of N-acetyl-phenylalanyl-NH2 by RHF, DFT, and MP2 computation and AIM analyses, confirmed by jet-cooled infrared data.

Computational and experimental determinations were carried out in parallel on the conformational probability of N-Acetyl-Phenylalanine-NH2 (NAPA). Ab initio computations were completed at the BLYP/6-311G(df,p), B3LYP/6-31G(d), B3LYP/6-31G(d,p), and B3LYP/6-31+G(d) levels of theory, labeled L/61fp, B/6, B/6p, and B/6+, respectively. Three experimentally identified conformers were compared with theoretical data, confirming their identities as the betaLanti, gammaLgauche+, and gammaLgauche- (BACKBONESIDECHAIN) conformers. Evidence comes from matching experimental and theoretical data for all three constituent N-H stretches of NAPA, with a Delta(Experimental-Theoretical) = approximately 1-3 cm(-1), approximately 0-5 cm(-1), and approximately 1-6 cm(-1), at the L/61fp and B/6+ levels, respectively. Corrected-ZPE relative energies were computed to be 0.14, 0.00, 0.26 and 0.00, 0.67, 0.57 (kcal*mol(-1)) for the betaLanti, gammaLgauche+, and gamma(Lgauche- conformers, respectively, at the L/61fp and B/6+ levels, respectively. The MP2/6-31+G(d) level of theory was subsequently found to give similar relative energies. Characterization of the intramolecular interactions responsible for red and blue shifting of the N-H stretches showed the existence of the following intramolecular interactions: C=O[i]- - -HN[i], (Ar[i])-Cgamma- - -HN[i+1], (Ar[i])-Cdelta-H- - -O=C[i-1] for betaLanti; C=O[i-1]- - -HN[i+1], (Ar[i])-Cgamma- - -HN[i+1], (Ar[i])-C-H- - -O=C[i] for gammaLgauche+; and C=O[i-1]- - -HN[i+1] for gammaLgauche-. Each of these interactions were further investigated and subsequently characterized by orbital population and Atoms-In-Molecules (AIM) analyses, with the identity of overlap and bond critical points (BCP) serving as 'scoring criteria', respectively. Experimental and theoretical carbonyl stretches were also compared and showed good agreement, adding further strength to the synergy between experiment and theory.