Possible molecular basis of the biochemical effects of cysteine-derived persulfides

Persulfides (RSSH/RSS−) are species closely related to thiols (RSH/RS−) and hydrogen sulfide (H2S/HS−), and can be formed in biological systems in both low and high molecular weight cysteine-containing compounds. They are key intermediates in catabolic and biosynthetic processes, and have been proposed to participate in the transduction of hydrogen sulfide effects. Persulfides are acidic, more acidic than thiols, and the persulfide anions are expected to be the predominant species at neutral pH. The persulfide anion has high nucleophilicity, due in part to the alpha effect, i.e., the increased reactivity of a nucleophile when the neighboring atom has high electron density. In addition, persulfides have electrophilic character, a property that is absent in both thiols and hydrogen sulfide. In this article, the biochemistry of persulfides is described, and the possible ways in which the formation of a persulfide could impact on the properties of the biomolecule involved are discussed

Minimum free energy pathways with the nudged elastic band method in combination with a QM-MM Hamiltonian

The optimization of minimum free energy pathways (MFEP) is one of the most widely used strategies to study activated processes. For chemical reactions, this requires the use of quantum mechanics. Using quantum mechanics molecular mechanics (QM- MM) Hamiltionians allows the simulation of reactive processes in complex environments by treating with quantum mechanics only the chemically relevant part of the system. However, even within this approximation, the affordable simulation lenghts of QM-MM simulations is in general, quite limited. Free energy methods based on the sampling of the potential energy surface require long simulations times to provide converged and accurate results. As consequence, the combination of QM-MM methods and free energy calculations is computationally expensive. Moreover, the user usually needs to perform an a priori selection of the reaction coordinate. This may be not trivial for the general case. One of the most established methods for finding potential energy profiles without selecting a reaction coordinate is the nudged elastic band method (NEB). In this work, we used the extension of this method to the exploration of the free energy surface for finding MFEP (FENEB). We present and apply to reactive systems an improved version of the basic optimization scheme of FENEB that increases its robustness, and is based on decoupling the optimization of the band in the perpendicular direction to the band, from the optimization of the tangential direction. In each optimization step, a full optimization with the spring force is performed, in order to keep the images evenly distributed. Additionally, we evaluate the influence of sampling in the quality of the optimized MFEP and free energy barrier computed from it. We show and discuss that the FENEB method provides a good estimation of the reaction barrier even with relatively short simulations lenghts and that it scales better than umbrella sampling both with simulation lenght and with dimensionality. Overall, our results support that the combination of QM-MM methods and the FENEB provides an adequate tool study chemical processes in complex environments

Molecular structure effects on the kinetics of hydroxyl radical addition to azo dyes

The effect of the molecular structure of azobenzene and related azo dyes on their reactivity towards .OH radicals in water was investigated by performing ultrasonic irradiation experiments on their aqueous solutions and density functional theory (DFT) calculations. Sonolysis of azobenzene, methyl orange, o-methyl red and p-methyl red was performed at a frequency of 500 kHz and 50 W applied power under air saturation. Under such irradiation conditions, these molecules were shown to decompose through .OH radical addition reactions taking place in the bulk liquid. The ortho isomer of methyl red reacted at significantly higher rates (nearly 30% higher) than the other three studied compounds in non-buffered aqueous solutions. In contrast, measurements performed at lower pH (10 mM HNO3), at which the carboxylic group vicinal to the azo group is protonated, yielded a similar reaction rate for all four substrates, i.e. the specific acceleration observed in the ortho-substituted dye disappeared with protonation. These results were rationalized by the computation of formation energies of the adduct originated in the .OH addition to the azo group, performing DFT calculations combined with the polarized continuum model (PCM) of solvation. The calculations suggest that intramolecular H-bonding in the o-methyl red–OH adduct provides extra stabilization in that particular case, which correlates with the observed higher addition rates of .OH radical to the anionic form of that isomer in non-buffered solutions. On the other hand, the energy changes calculated for the .OH addition to an o-methyl red molecule which is protonated in the carboxylic group (representative of the situation at pH 2) do not differ significantly from those computed for the other three molecules studied

Tertiary and quaternary structural basis of oxygen affinity in human hemoglobin as revealed by multiscale simulations

Abstract Human hemoglobin (Hb) is a benchmark protein of structural biology that shaped our view of allosterism over 60 years ago, with the introduction of the MWC model based on Perutz structures of the oxy(R) and deoxy(T) states and the more recent Tertiary Two-State model that proposed the existence of individual subunit states -“r” and “t”-, whose structure is yet unknown. Cooperative oxygen binding is essential for Hb function, and despite decades of research there are still open questions related to how tertiary and quaternary changes regulate oxygen affinity. In the present work, we have determined the free energy profiles of oxygen migration and for HisE7 gate opening, with QM/MM calculations of the oxygen binding energy in order to address the influence of tertiary differences in the control of oxygen affinity. Our results show that in the α subunit the low to high affinity transition is achieved by a proximal effect that mostly affects oxygen dissociation and is the driving force of the allosteric transition, while in the β subunit the affinity change results from a complex interplay of proximal and distal effects, including an increase in the HE7 gate opening, that as shown by free energy profiles promotes oxygen uptake

Structure and Bonding in Pentacyano(L)ferrate(II) and Pentacyano(L)ruthenate(II) Complexes (L = Pyridine, Pyrazine, and N-Methylpyrazinium): A Density Functional Study

Density Functional Theory (DFT) at the generalized gradient approximation (GGA) level has been applied to the complexes [Fe(CN)5L]n- and [Ru(CN)5L]n- (L = pyridine, pyrazine, N-methylpyrazinium), as well as to [Fe(CN)5]3- and [Ru(CN)5]3-. Full geometry optimizations have been performed in all cases. The geometrical parameters are in good agreement with available information for related systems. The role of the MII-L back-bonding was investigated by means of a L and cyanide Mulliken population analysis. For both Fe(II) and Ru(II) complexes the metal-L dissociation energies follow the ordering pyridine < pyrazine < N-methyl pyrazinium, consistent with the predicted σ-donating and π*-accepting abilities of the L ligands. Also, the computed metal-L bond dissociation energies are systematically smaller in the Ru(II) than in the Fe(II) complexes. This fact suggests that previous interpretations of kinetic data, showing that ruthenium complexes in aqueous solution are more inert than their iron analogues, are not related to a stronger Ru-L bond but are probably due to solvation effects