Theoretical Study on HF Elimination and Aromatization Mechanisms: A Case of Pyridoxal 5′ Phosphate-Dependent Enzyme

Pyridoxal 5-phosphate (PLP), the phosphorylated and the oxidized form of vitamin B6 is an organic cofactor. PLP forms a Schiff base with the ϵ-amino group of a lysine residue of PLP-dependent enzymes. γ-Aminobutyric acid (GABA) aminotransferase is a PLP-dependent enzyme that degrades GABA to succinic semialdehyde, while reduction of GABA concentration in the brain causes convolution besides several neurological diseases. The fluorine-containing substrate analogues for the inactivation of the GABA-AT are synthesized extensively in cases where the inactivation mechanisms involve HF elimination. Although two proposed mechanisms are present for the HF elimination, the details of the base-induced HF elimination are not well identified. In this density functional theory (DFT) study, fluorine-containing substrate analogue, 5-amino-2-fluorocyclohex-3-enecarboxylic acid, is particularly chosen in order to explain the details of the HF elimination reactions. On the other hand, the experimental studies revealed that aromatization competes with Michael addition mechanism in the presence of 5-amino-2-fluorocyclohex-3-enecarboxylic acid. The results allowed us to draw a conclusion for the nature of HF elimination, besides the elucidation of the mechanism preference for the inactivation mechanism. Furthermore, the solvent phase calculations carried out in this study ensure that the proton transfer steps should be assisted either by a water molecule or a base for lower activation energy barriers

A Theoretical Study On Rh(I) Catalyzed Enantioselective Conjugate Addition Reactions of Fluoroalkylated Olefins

In this study, quantum mechanical calculations have been performed to elucidate the mechanism and enantioselectivity in rhodium-catalyzed 1,4-conjugate addition reaction of a series of aryl groups to electron-deficient 4,4,4-trifluoro-1-phenyl-2-buten-1-one in the presence of (<i>S</i>)-BINAP. Conjugate addition of unsubstituted, <i>o</i>-CH₃, <i>p</i>- and <i>o</i>-Cl substituted phenyl groups were considered to explain steric and electronic effects on the reaction mechanism. The activation energy difference between benzene and <i>o</i>-toluene-substituted systems (8.1 kcal/mol for the <i>R</i> isomer) has shown the impact of steric effects of substituents at the ortho position. The electronic effect of a Cl substituent at the ortho position was demonstrated by an even higher energy barrier (11.9 kcal/mol of energy difference between benzene and <i>o</i>-Cl for R enantiomer). The experimental unreactivity of the <i>o</i>-Cl-substituted system was also confirmed with the calculated high activation energies for both <i>R</i> and <i>S</i> (29.9 and 31.7 kcal/mol for <i>R</i> and <i>S</i>, respectively) product formations. The system with para-positioned Cl revealed almost the same barriers for benzene, indicating that substituents at the para position do not have significant electronic or steric effects in this reaction. In all the modeled sets, experimental <i>R</i> product predominance could be reproduced. The quantitative trend was satisfied with the B3LYP/6-31G* functional, where the LANL2DZ effective core potential was used for Rh, P, S, and Cl atoms. Benchmark calculations have been performed to validate the level of theory in this study

Role of the <i>n</i>+1 amino acid residue on the deamidation of asparagine in pentapeptides

<div><p>Deamidation plays an important role in biochemical phenomena such as aging. The role of the <i>n</i> + 1 residue on the deamidation of asparagine (asparagine being the <i>n</i>th residue) in three pentapeptide chains (GGNGG, GGNMG and GGNIG) has been analysed with hybrid computational tools. Potentials of mean force at 300 K were calculated from the MD/replica exchange simulations using weighted histogram analysis (WHAM) in explicit water. The snapshots were clustered taking into account the requirements of the plausible deamidation mechanisms, as such the tautomerisation of the asparagine side chain as initial step has been confirmed, based on the proximity of water to the deamidation site. The ultimate goal being to gain an insight on the peptide backbone N-H acidity, quantum mechanical calculations have been carried out. For this purpose, the distribution of Φ/Ψ, Φ₂/Ψ and end-to-end distances  deduced from the WHAM diagrams have been considered and a total of 110 structures have been sampled. These neutral pentapeptides as well as their corresponding anions have been optimised (B3LYP/6-31++G(d,p)) in implicit water in order to gain an insight on the peptide backbone N-H acidity. In this study, we have shown that the open conformations of the neutrals and the anions, which display a β sheet like structure are well populated and their <i>pK_a</i>s rank in the same order as the deamidating half-lives, that is the peptides that deaminate fastest can more readily access conformations that are more acidic.</p></div