The catalytic mechanism of glyceraldehyde 3-phosphate dehydrogenase from Trypanosoma cruzi elucidated via the QM/MM approach.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as a key enzyme involved in glycolysis processes for energy production in the Trypanosoma cruzi parasite. This enzyme catalyses the oxidative phosphorylation of glyceraldehyde 3-phosphate (G3P) in the presence of inorganic phosphate (Pi) and nicotinamide adenosine dinucleotide (NAD+). The catalytic mechanism used by GAPDH has been intensively investigated. However, the individual roles of Pi and the C3 phosphate of G3P (Ps) sites, as well as some residues such as His194 in the catalytic mechanism, remain unclear. In this study, we have employed Molecular Dynamics (MD) simulations within hybrid quantum mechanical/molecular mechanical (QM/MM) potentials to obtain the Potential of Mean Force of the catalytic oxidative phosphorylation mechanism of the G3P substrate used by GAPDH. According to our results, the first stage of the reaction (oxidoreduction) takes place in the Pi site (energetically more favourable), with the formation of oxyanion thiohemiacetal and thioacylenzyme intermediates without acid-base assistance of His194. Analysis of the interaction energy by residues shows that Arg249 has an important role in the ability of the enzyme to bind the G3P substrate, which interacts with NAD+ and other important residues, such as Cys166, Glu109, Thr167, Ser247 and Thr226, in the GAPDH active site. Finally, the inhibition mechanism of the GAPDH enzyme by the 3-(p-nitrophenoxycarboxyl)-3-ethylene propyl dihydroxyphosphonate inhibitor was investigated in order to contribute to the design of new inhibitors of GAPDH from Trypanosoma cruzi.

A theoretical study of phenolic compounds with antioxidant properties.

Quantum chemical calculations at the DFT/B3LYP, HF, and AM1 and PM3 semiempirical levels were employed to calculate a set of molecular properties for 41 phenol compounds with antioxidant activity. The significant molecular descriptors related to the compounds were the vertical ionization potentials (IPvs) and the charge on oxygen atom 7. The IPv has been calculated using Koopman's theorem IPv=-epsilon(HOMO(DFT)), IPv=-epsilon(HOMO(HF)) and as the difference of energy calculations for the corresponding cation and for the neutral form IPv(E(cation)-E(neutral)) obtained with the DFT/B3LYP method. The best model obtained showed not only the statistical significance but also predictive ability.

Endovascular treatment of basilar tip aneurysms with Guglielmi detachable coils: predictors of immediate and long-term results with multivariate analysis 6-year experience.

PURPOSE: To analyze anatomic and clinical results and factors predictive of outcome in treatment of basilar tip aneurysms with Guglielmi detachable coils (GDCs). MATERIALS AND METHODS: During 6 years, 55 unselected consecutive saccular aneurysms in 53 patients (mean age, 47 years) were treated with GDC occlusion. Forty-one (75%) aneurysms were ruptured (Hunt-Hess and Fisher grades were assigned in patients); 14 (25%), unruptured. Clinical and angiographic evaluations were performed 6 months after treatment and during follow-up (mean follow-up, 2 years). Multivariate analysis was used to determine factors predictive of outcome. RESULTS: GDC occlusion was a success in 52 (95%) aneurysms, a failure in two (4%), and not attempted in one (2%). Occlusion at final follow-up, evaluated in 44 aneurysms, was complete in 34 (77%), near complete in four (9%), and incomplete in six (14%). At 6-12 months, mean aneurysmal occlusion rate significantly worsened because of revascularization (P <.001) but improved at final follow-up because of reembolization in 10 aneurysms (P =.009); it remained stable (P =.351) between initial and final follow-up. Multivariate binary logistic regression indicated that before treatment started, aneurysmal neck size was the only independent predictor of initial occlusion rate (P =.002) and revascularization (P =.004). After the initial procedure, sac size and initial occlusion rate were independent predictors of revascularization (P =.004 and.008, respectively), irrespective of neck size. Occlusion rate at 6-12-month follow-up was the only independent predictor of that at final follow-up (P =.021), regardless of shape of aneurysm. Overall morbidity was 2% (one of 51); mortality, 6% (three of 51). Mortality correlated significantly with Hunt-Hess grade 4 at admission (P =.003) and incidence of vasospasm (P =.058). CONCLUSION: GDC occlusion proved to be a safe effective therapeutic alternative to surgery in patients with ruptured or unruptured basilar tip aneurysms. Morphologic and clinical factors were respectively identified as predictors of the optimal anatomic and clinical outcomes.