Abstract:Direct electron transfer (ET) of redox proteins immobilized on biomimetic or biocompatible electrodes represents an active field of fundamental and applied research. In this context, several groups have reported for a variety of proteins unexpected distance dependencies of the ET rate, whose origin remains largely speculative and controversial, but appears to be a quite general phenomenon. Here we have employed molecular dynamics (MD) simulations and electron pathway analyses to study the ET properties of cyto… Show more
“…In fact, the study of the Cyt 552 -Cu A complex reveals subtle structural perturbations at the Cu A site in a redox state-dependent fashion (13). In addition, the prediction that moderate electric fields alter the barrier for σ u *-π u interchange suggests that the local membrane potential could exert regulation on the electroprotonic energy transduction, as previously proposed based on different evidence (31,32). Of utmost importance, however, even in the absence of external perturbations, the enhanced superexchange coupling of the π u state renders it suitable for participating in the ET reaction, even if poorly populated.…”
Electron transfer is the simplest chemical reaction and constitutes the basis of a large variety of biological processes, such as photosynthesis and cellular respiration. Nature has evolved specific proteins and cofactors for these functions. The mechanisms optimizing biological electron transfer have been matter of intense debate, such as the role of the protein milieu between donor and acceptor sites. Here we propose a mechanism regulating longrange electron transfer in proteins. Specifically, we report a spectroscopic, electrochemical, and theoretical study on WT and singlemutant Cu A redox centers from Thermus thermophilus, which shows that thermal fluctuations may populate two alternative ground-state electronic wave functions optimized for electron entry and exit, respectively, through two different and nearly perpendicular pathways. These findings suggest a unique role for alternative or "invisible" electronic ground states in directional electron transfer. Moreover, it is shown that this energy gap and, therefore, the equilibrium between ground states can be fine-tuned by minor perturbations, suggesting alternative ways through which protein-protein interactions and membrane potential may optimize and regulate electron-proton energy transduction.cytochrome oxidase | invisible states | paramagnetic proteins | NMR | spectroscopy
“…In fact, the study of the Cyt 552 -Cu A complex reveals subtle structural perturbations at the Cu A site in a redox state-dependent fashion (13). In addition, the prediction that moderate electric fields alter the barrier for σ u *-π u interchange suggests that the local membrane potential could exert regulation on the electroprotonic energy transduction, as previously proposed based on different evidence (31,32). Of utmost importance, however, even in the absence of external perturbations, the enhanced superexchange coupling of the π u state renders it suitable for participating in the ET reaction, even if poorly populated.…”
Electron transfer is the simplest chemical reaction and constitutes the basis of a large variety of biological processes, such as photosynthesis and cellular respiration. Nature has evolved specific proteins and cofactors for these functions. The mechanisms optimizing biological electron transfer have been matter of intense debate, such as the role of the protein milieu between donor and acceptor sites. Here we propose a mechanism regulating longrange electron transfer in proteins. Specifically, we report a spectroscopic, electrochemical, and theoretical study on WT and singlemutant Cu A redox centers from Thermus thermophilus, which shows that thermal fluctuations may populate two alternative ground-state electronic wave functions optimized for electron entry and exit, respectively, through two different and nearly perpendicular pathways. These findings suggest a unique role for alternative or "invisible" electronic ground states in directional electron transfer. Moreover, it is shown that this energy gap and, therefore, the equilibrium between ground states can be fine-tuned by minor perturbations, suggesting alternative ways through which protein-protein interactions and membrane potential may optimize and regulate electron-proton energy transduction.cytochrome oxidase | invisible states | paramagnetic proteins | NMR | spectroscopy
“…The probability of ET toward the ferryl-oxoheme group was calculated using the pathways algorithm (56,57). This method looks for the best possible path connecting the electron donor and the acceptor, and it was successfully used by our group previously (58)(59)(60)(61)(62). Briefly, according to the Marcus theory (63), the ET rate constant (k ET ) depends on the reaction standard free energy (ΔG°), the reorganization energy (λ), and the electronic coupling matrix (T DA ), described in the following equation:…”
The Trypanosoma cruzi ascorbate peroxidase is, by sequence analysis, a hybrid type A member of class I heme peroxidases [TcAPx-cytochrome c peroxidase (CcP)], suggesting both ascorbate (Asc) and cytochrome c (Cc) peroxidase activity. Here, we show that the enzyme reacts fast with H 2 O 2 (k = 2.9 × 10 7 M −1 ·s −1 ) and catalytically decomposes H 2 O 2 using Cc as the reducing substrate with higher efficiency than Asc (k cat /K m = 2.1 × 10 5 versus 3.5 × 10 4 M −1 ·s −1 , respectively). Visible-absorption spectra of purified recombinant TcAPx-CcP after H 2 O 2 reaction denote the formation of a compound I-like product, characteristic of the generation of a tryptophanyl radical-cation (Trp 233•+ ). Mutation of Trp 233 to phenylalanine (W233F) completely abolishes the Cc-dependent peroxidase activity. In addition to Trp 233•+ , a Cys 222 -derived radical was identified by electron paramagnetic resonance spin trapping, immunospin trapping, and MS analysis after equimolar H 2 O 2 addition, supporting an alternative electron transfer (ET) pathway from the heme. Molecular dynamics studies revealed that ET between Trp 233 and Cys 222 is possible and likely to participate in the catalytic cycle. Recognizing the ability of TcAPx-CcP to use alternative reducing substrates, we searched for its subcellular localization in the infective parasite stages (intracellular amastigotes and extracellular trypomastigotes). TcAPx-CcP was found closely associated with mitochondrial membranes and, most interestingly, with the outer leaflet of the plasma membrane, suggesting a role at the host-parasite interface. TcAPx-CcP overexpressers were significantly more infective to macrophages and cardiomyocytes, as well as in the mouse model of Chagas disease, supporting the involvement of TcAPx-CcP in pathogen virulence as part of the parasite antioxidant armamentarium.Trypanosoma cruzi | heme peroxidase | oxidants | virulence | kinetics
“…The properties of SAMs have been reviewed in (Chaki & Vijayamohanan, 2002;Gooding et al 2003;Love et al 2005;Senaratne et al 2005). Modeling of protein-SAM interactions has been reported, mostly for alkanethiol SAMs, in (Alvarez-Paggi et al 2010;Hsu et al 2008;O'Mahony et al 2013;Sun et al 2005;Utesch et al 2013;Wang et al 2010a, b;Xie et al 2012) and peptide-SAM interactions have been modeled by Nowinski et al (2012).…”
Section: Self-assembled Monolayersmentioning
confidence: 99%
“…Examples include simulations for structural refinement of docked complexes (Aliaga et al 2011;Alvarez-Paggi et al 2013;Brancolini et al 2012Brancolini et al , 2015Imamura et al 2007), and for the investigation of the binding orientations of proteins on surfaces (Alvarez-Paggi et al 2010;Boughton et al 2010;Coppage et al 2013); the kinetic mechanisms of adsorption (Raffaini & Ganazzoli, 2010); the ET pathways and properties of adsorbed proteins (Bizzarri, 2006;Siwko & Corni, 2013;Utesch et al 2012;Zanetti-Polzi et al 2014;Zhou et al 2004); the effects of pH (Emami et al 2014b;Imamura et al 2003;Tosaka et al 2010;Utesch et al 2013) and ionic strength (Bizzarri, 2006) on adsorption; the role of ions in mediating adsorption ; and structural and energetic aspects of adsorption of proteins on surfaces (Apicella et al 2013;Jose & Sengupta, 2013;Hoefling et al 2011;Hung et al 2011;Kubiak-Ossowska & Mulheran, 2010a, b;O'Mahony et al 2013;Vila Verde et al 2009Wang et al 2010a, b;Yu et al 2012a;Steckbeck et al 2014;Sun et al 2014a;Sun et al 2014b). Further, conventional MD can be used to simulate physical perturbations, such as mechanical or electrical forces exerted on molecules in experiments.…”
Abstract. Understanding protein-inorganic surface interactions is central to the rational design of new tools in biomaterial sciences, nanobiotechnology and nanomedicine. Although a significant amount of experimental research on protein adsorption onto solid substrates has been reported, many aspects of the recognition and interaction mechanisms of biomolecules and inorganic surfaces are still unclear. Theoretical modeling and simulations provide complementary approaches for experimental studies, and they have been applied for exploring protein-surface binding mechanisms, the determinants of binding specificity towards different surfaces, as well as the thermodynamics and kinetics of adsorption. Although the general computational approaches employed to study the dynamics of proteins and materials are similar, the models and force-fields (FFs) used for describing the physical properties and interactions of material surfaces and biological molecules differ. In particular, FF and water models designed for use in biomolecular simulations are often not directly transferable to surface simulations and vice versa. The adsorption events span a wide range of time-and length-scales that vary from nanoseconds to days, and from nanometers to micrometers, respectively, rendering the use of multi-scale approaches unavoidable. Further, changes in the atomic structure of material surfaces that can lead to surface reconstruction, and in the structure of proteins that can result in complete denaturation of the adsorbed molecules, can create many intermediate structural and energetic states that complicate sampling. In this review, we address the challenges posed to theoretical and computational methods in achieving accurate descriptions of the physical, chemical and mechanical properties of protein-surface systems. In this context, we discuss the applicability of different modeling and simulation techniques ranging from quantum mechanics through all-atom molecular mechanics to coarse-grained approaches. We examine uses of different sampling methods, as well as free energy calculations. Furthermore, we review computational studies of protein-surface interactions and discuss the successes and limitations of current approaches.
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