6 research outputs found

    Multiscale Modeling of Thiol Overoxidation in Peroxiredoxins by Hydrogen Peroxide

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    In this work, we employ a multiscale quantum-classical mechanics (QM/MM) scheme to investigate the chemical reactivity of sulfenic acids toward hydrogen peroxide, both in aqueous solution and in the protein environment of the peroxiredoxin alkyl hydroperoxide reductase E from Mycobacterium tuberculosis (MtAhpE). The reaction of oxidation of cysteine with hydrogen peroxides, catalyzed by peroxiredoxins, is usually accelerated several orders of magnitude in comparison with the analogous reaction in solution. The resulting cysteine sulfenic acid is then reduced in other steps of the catalytic cycle, recovering the original thiol. However, under some conditions, the sulfenic acid can react with another equivalent of oxidant to form a sulfinic acid. This process is called overoxidation and has been associated with redox signaling. Herein, we employed a multiscale scheme based on density function theory calculations coupled to the classical AMBER force field, developed in our group, to establish the molecular basis of thiol overoxidation by hydrogen peroxide. Our results suggest that residues that play key catalytic roles in the oxidation of MtAhpE are not relevant in the overoxidation process. Indeed, the calculations propose that the process is unfavored by this particular enzyme microenvironment.Fil: Semelak, Jonathan Alexis. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Ciudad Universitaria. Instituto de QuĂ­mica, FĂ­sica de los Materiales, Medioambiente y EnergĂ­a. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de QuĂ­mica, FĂ­sica de los Materiales, Medioambiente y EnergĂ­a; ArgentinaFil: Battistini, F.. Barcelona Institute of Science and Technology; EspañaFil: Radi, R.. Universidad de la RepĂșblica; UruguayFil: Trujillo, M.. Universidad de la RepĂșblica; UruguayFil: Zeida, A.. Universidad de la RepĂșblica; UruguayFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Ciudad Universitaria. Instituto de QuĂ­mica, FĂ­sica de los Materiales, Medioambiente y EnergĂ­a. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de QuĂ­mica, FĂ­sica de los Materiales, Medioambiente y EnergĂ­a; Argentin

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

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    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

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    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

    Chemical Reactivity and Spectroscopy Explored From QM/MM Molecular Dynamics Simulations Using the LIO Code

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    In this work we present the current advances in the development and the applications of LIO, a lab-made code designed for density functional theory calculations in graphical processing units (GPU), that can be coupled with different classical molecular dynamics engines. This code has been thoroughly optimized to perform efficient molecular dynamics simulations at the QM/MM DFT level, allowing for an exhaustive sampling of the configurational space. Selected examples are presented for the description of chemical reactivity in terms of free energy profiles, and also for the computation of optical properties, such as vibrational and electronic spectra in solvent and protein environments

    The “Carbonyl-Lock” Mechanism Underlying Non-Aromatic Fluorescence in Biological Matter

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    Challenging the basis of our chemical intuition, recent experimental evidence reveals the presence of a new type of intrinsic fluorescence in biomolecules that exists even in the absence of aromatic or electronically conjugated chemical compounds. The origin of this phenomenon has remained elusive so far. In the present study, we identify a mechanism underlying this new type of fluorescence in different biological aggregates. By employing non-adiabatic ab initio molecular dynamics simulations combined with an unsupervised learning approach, we characterize the typical ultrafast non-radiative relaxation pathways active in non-fluorescent peptides. We show that the key vibrational mode for the non-radiative decay towards the ground state is the carbonyl elongation. Non-aromatic fluorescence appears to emerge from blocking this mode with strong local interactions such as hydrogen bonds. This "carbonyl-lock" mechanism for trapping the excited state leads to the fluorescence yield increase observed experimentally, and paves the way for design principles to realize novel non-invasive biocompatible probes with applications in bioimaging, sensing, and biophotonics
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