Dissociation Free Energy Research Articles

Determination of the N-H Bond Dissociation Free Energy in a Pyridine(diimine)molybdenum Complex Prepared by Proton-Coupled Electron Transfer.

The pyridine(diimine)molybdenum bis(imido) complex (iPrPDI)Mo(═NTol)2 (Tol = 4-methylphenyl) was synthesized by the addition of 2 equiv of 4-methylphenylazide to the corresponding molybdenum benzene derivative, (iPrPDI)Mo(η6-C6H6) [iPrPDI = 2,6-(2,6-iPr2C6H3N═CMe)2C5H3N]. Protonation of (iPrPDI)Mo(═NTol)2 with 2,6-lutinidum triflate yielded a cationic molybdenum amido complex, [(iPrPDI)Mo(NHTol)(═NTol)][OTf], which was further transformed into the neutral molybdenum amido (iPrPDI)Mo(NHTol)(═NTol) by reduction with zinc powder. A series of spectroscopic, synthetic, and pKa determination studies along with electrochemical measurements by the protonation-reduction pathway were used to establish an N-H bond dissociation free energy (BDFE) between 65 and 69 kcal/mol for the molybdenum imido-amido compound, (iPrPDI)Mo(NHTol)(═NTol). Full-molecule density functional theory studies provided a computed value of 61 kcal/mol. By contrast, reduction of (iPrPDI)Mo(═NTol)2 with KC8 afforded the corresponding anionic molybdenum complex K[(iPrPDI)Mo(═NTol)2], which has a potassium cation intercalated with the pyridine and tolyl groups. Protonation of K[(iPrPDI)Mo(═NTol)2] with the weak amidinium acid [TBD(H)][BArF24] (TBD = triazabicyclodecene; BArF24 = B[3,5-(CF3)2C6H3]4) also produced the neutral molybdenum amido complex (iPrPDI)Mo(NHTol)(═NTol). Measurement of the pKa and oxidation potential of K[(iPrPDI)Mo(═NTol)2] provided a range of 69-73 kcal/mol for the N-H BDFE of (iPrPDI)Mo(NHTol)(═NTol), in good agreement with the protonation-reduction route and completing the square scheme. The similar pKa and redox potentials obtained from each pathway demonstrate that both sequences are energetically feasible for proton-coupled electron-transfer (PCET) events. This study on the determination of N-H BDFE of the molybdenum amido complex renders fundamental insight into the N2 reduction cycle by PCET.

Systematic Trends in the Electrochemical Properties of Transition Metal Hydride Complexes Discovered by Using the Ligand Acidity Constant Equation.

Understanding the thermodynamics of paramagnetic transition metal hydride complexes, especially of the abundant 3d metals, is important in the design of electrocatalysts and organometallic catalysts. The pKaMeCN([MHLn]+/[MLn) of paramagnetic hydrides in MeCN are estimated for the first time using the ligand acidity constant (LAC) equation where contributions to the pKaMeCN from each ligand are simply added together, with the sum corrected for effects of charge and 5d metals. The pKaLAC-MeCN([MHLn]+/MLn) of over 200 hydride complexes MHLn are used, along with their electrochemical potentials from the literature, in an uncommonly applied thermochemical cycle in order to reveal systematic trends in the redox couples MIII/II and MV/IV (M = Cr, Mo, W), MnII/I, ReVI/V and ReIV/III, MIII/II and MIV/III (M = Fe, Ru, Os), and MIII/II and MII/I (M = Co, Rh, and Ir) and allow the estimation of the bond dissociation free energies BDFE(MH) of the unoxidized hydrides MHLn and the prediction of the electrochemical potential for their oxidation. Density functional theory (DFT) calculations are used to validate the pKaLAC-MeCN values of hydrides of WIII, MnII, FeIII, RuIII, CoII, and NiIII. When a pKaLAC-MeCN is less than zero for a given complex [MHLn]+, the oxidation of MHLn is irreversible due to proton loss from the oxidized complex to the solvent. When pKaLAC-MeCN ≫ 0, the oxidation is reversible when there is no gross change in the coordination geometry upon a change in the redox state. Twenty paramagnetic hydrides prepared in bulk all have pKaLAC-MeCN > 8.

Exceptionally High O-H Bond Dissociation Free Energy of a Dicopper(II) μ-Hydroxo Complex and Insights into the Geometric and Electronic Structure Origins Thereof.

The strength of the relevant bonds in bond-making and bond-breaking processes can directly affect the overall efficiency of the process. Copper-oxygen sites are known to catalyze reactions with some of the most recalcitrant C-H bonds found in nature as quantified by the bond dissociation free energy (BDFE), yet only a handful of copper-bound O-H bond strengths have been defined. Equally important in the design of synthetic catalysts is an understanding of the geometric and electronic structure origins of these thermodynamic parameters. In this report, the BDFE(OH) of two dicopper-hydroxo complexes, {[LCu]2-(μ-OH)}3+ and {[LCu]2-(μ-OH)}4+ (L = tris(2-pyridylmethyl)amine), were measured. Two key observations were made: (i) the BDFE(OH)s of these complexes were exceptionally high at 103.4 and 91.7 kcal/mol, respectively, which are the highest condensed phase MO-H BDFEs to date and (ii) that the higher oxidation state had a lower BDFE(OH), which is counter to expectations based on known mononuclear BDFE(OH)s which increase with the oxidation state. To understand the origin of these thermodynamic values, the BDFE(OH)s were measured and analyzed for the mononuclear complexes [LCu(OH2)]1+ and [LCu(OH2)]2+ in the same ligand environment. This treatment revealed "dinuclear effects" that include contributions from rehybridization of the oxygen, mixed valency of the metals, magnetic exchange between the metals, and differences in solvation, which are general with respect to [M]2-OH complexes to varying degrees. These analyses are important because they provide a starting point for rationally tuning the thermodynamics of catalytic intermediates broadly and for understanding how copper active sites achieve activation of strong C-H bonds.

Noble Gas Binding Ability of an Au(I) Cation Stabilized by a Frustrated Lewis Pair: A DFT Study.

The noble gas (Ng) binding ability of a monocationic [(FLP)Au]+ species has been investigated by a computational study. Here, the monocationic [(FLP)Au]+ species is formed by coordination of Au(I) cation with the phosphorous (Lewis base) and the boron (Lewis acid) centers of a frustrated Lewis pair (FLP). The bonds involving Au and P, and Au and B atoms in [(FLP)Au]+ are partially covalent in nature as revealed by Wiberg bond index (WBI) values, electron density analysis and energy decomposition analysis (EDA). The zero point energy corrected bond dissociation energy (D0), enthalpy and free energy changes are computed for the dissociation of Au-Ng bonds to assess the Ng binding ability of [(FLP)Au]+ species. The D0 ranges from 6.0 to 13.3 kcal/mol, which increases from Ar to Rn. Moreover, the dissociation of Au-Ng bonds is endothermic as well as endergonic for Ng = Kr-Rn, whereas the same for Ng = Ar is endothermic but exergonic at room temperature. The partial covalent character of the bonds between Au and Ng atoms is demonstrated by their WBI values and electron density analysis. The Ng atoms get slight positive charges of 0.11–0.23 |e|, which indicates some amount of charge transfer takes place from it. EDA demonstrates that electrostatic and orbital interactions have equal contributions to stabilize the Ng-Au bonds in the [(FLP)AuNg]+ complex.

Phenol Oxidation by a Nickel(III)-Fluoride Complex: Exploring the Influence of the Proton Accepting Ligand in PCET Oxidation.

In order to gain insight into the influence of the H+ -accepting terminal ligand in high-valent oxidant mediated proton coupled electron transfer (PCET) reactions, the reactivity of a high valent nickel-fluoride complex [NiIII (F)(L)] (2, L=N,N'-(2,6-dimethylphenyl)-2,6-pyridinecarboxamidate) with substituted phenols was explored. Analysis of kinetic data from these reactions (Evans-Polanyi, Hammett, and Marcus plots, and KIE measurements) and the formed products show that 2 reacted with electron rich phenols through a hydrogen atom transfer (HAT, or concerted PCET) mechanism and with electron poor phenols through a stepwise proton transfer/electron transfer (PT/ET) reaction mechanism. The analogous complexes [NiIII (Z)(L)] (Z=Cl, OCO2 H, O2 CCH3 , ONO2 ) reacted with all phenols through a HAT mechanism. We explore the reason for a change in mechanism with the highly basic fluoride ligand in 2. Complex 2 was also found to react one to two orders of magnitude faster than the corresponding analogous [NiIII (Z)(L)] complexes. This was ascribed to a high bond dissociation free energy value associated with H-F (135 kcal mol-1 ), which is postulated to be the product formed from PCET oxidation by 2 and is believed to be the driving force for the reaction. Our findings show that high-valent metal-fluoride complexes represent a class of highly reactive PCET oxidants.

Determining Proton-Coupled Standard Potentials and X–H Bond Dissociation Free Energies in Nonaqueous Solvents Using Open-Circuit Potential Measurements

Proton-coupled electron transfer (PCET) reactions are increasingly being studied in nonaqueous conditions, where the thermochemistry of PCET substrates is largely unknown. Herein, we report a method to obtain electrochemical standard potentials and calculate the corresponding bond dissociation free energies (BDFEs) of stable PCET reagents in nonaqueous solvents, using open-circuit potential (OCP) measurements. With this method, we measure PCET thermochemistry in acetonitrile and tetrahydrofuran for substrates with O-H and N-H bonds that undergo 1e-/1H+ and 2e-/2H+ redox processes. We also report corrected thermochemical values for the 1/2H2(g)/H•1M and H+/H• (CG) couples in several organic solvents. For 2e-/2H+ couples, OCP measurements provide the multielectron/multiproton standard potential and the average of the two X-H BDFEs. In contrast to traditional approaches for calculating BDFEs from electrochemical measurements, the OCP method directly measures the overall PCET reaction thermodynamics and avoids the need for a pKa scale in the solvent of interest. Consequently, the OCP approach yields more accurate thermochemical values and should be general to any solvent mixture compatible with electrochemical measurements. The longer time scale of OCP measurements enables accurate thermochemical measurements for redox couples with irreversible or distorted electrochemical responses by cyclic voltammetry, provided the PCET reaction is chemically reversible. Recommendations for successful OCP measurements and limitations of the approach are discussed, including the current inability to measure processes involving C-H bonds. As a straightforward and robust technique to determine nonaqueous PCET thermochemistry, these OCP measurements will be broadly valuable, with applications ranging from fundamental reactivity studies to device development.

QM/MM-MD dissociation of Ag+ and H+ mediated cytosine pairs: Monomers and dimers

We report a biased QM/MM molecular dynamics study of the dissociation process of cytosine-cytosine complexes mediated by Ag+ or H+ ions in monomeric and dimeric forms. We performed calculations under explicit solvent conditions and obtained the free energy profiles by thermodynamic integration technique to give deep insights on the dissociation process. For all geometries corresponding to key points on energy profiles the noncovalent interaction descriptors were calculated and the details of dissociation mechanism were revealed. Our findings by means of dissociation energy barrier analysis for Ag+-mediated cytosines suggested more favorable cis-configuration of C(Ag+)C with the energy of 17.8 kcal/mol over trans-configuration with the energy of 12.2 kcal/mol in monomeric form, in contrast to H+ mediated cytosines. Also, it is shown that the QM/MM-MD global minimum of dissociation free energy profiles for both monomer isomers (cis- and trans-) doesn’t correspond to the geometries found in crystal data and previous theoretical studies of equilibrium geometries. But the addition of an adjacent silver mediated cytosine pair, in which additional stabilizing factors arise such as interplane H-bonding, π-π stacking or argentophilic interaction, leads to a change in the dissociation profiles and improving the agreement with experiment. The trans-configuration of (C(Ag+)C)2 with the energy barrier of 16.6 kcal/mol is more favorable in the dissociation process then cis-configuration with the energy of 15.6 kcal/mol.

A Theoretical Study of the Adsorption Process of B-aflatoxins Using Pyracanthakoidzumii (Hayata) Rehder Biomasses.

Employing theoretical calculations with density functional theory (DFT) using the B3LYP/6-311++G(d,p) functional and basis set, the interaction of the aflatoxin B1 (AFB1) molecule and the functional groups present in the Pyracantha koidzumii biosorbent was investigated. Dissociation free energy and acidity equilibrium constant values were obtained theoretically both in solution (water) and gas phases. Additionally, the molecular electrostatic potential for the protonated molecules was calculated to verify the reactivity. Thus, methanol (hydroxyl group), methylammonium ion (amino group), acetate ion (carboxyl group), and acetone (carbonyl group), were used as representatives of the substrates present in the biomass; these references were considered using the corresponding protonated or unprotonated forms at a pH value of 5. The experimental infrared spectrophotometric data suggested the participation of these functional groups in the AFB1 biosorption process, indicating that the mechanism was dominated by electrostatic interactions between the charged functional groups and the positively charged AFB1 molecule. The theoretical determination indicated that the carboxylate ion provided the highest interaction energy with the AFB1 molecule. Consequently, an enriched biosorbent with compounds containing carboxyl groups could improve the yield of the AFB1 adsorption when using in vitro and in vivo trials.

Catalytic Hydrogenation of a Manganese(V) Nitride to Ammonia.

The catalytic hydrogenation of a metal nitride to produce free ammonia using a rhodium hydride catalyst that promotes H2 activation and hydrogen-atom transfer is described. The phenylimine-substituted rhodium complex (η5-C5Me5)Rh(MePhI)H (MePhI = N-methyl-1-phenylethan-1-imine) exhibited higher thermal stability compared to the previously reported (η5-C5Me5)Rh(ppy)H (ppy = 2-phenylpyridine). DFT calculations established that the two rhodium complexes have comparable Rh-H bond dissociation free energies of 51.8 kcal mol-1 for (η5-C5Me5)Rh(MePhI)H and 51.1 kcal mol-1 for (η5-C5Me5)Rh(ppy)H. In the presence of 10 mol% of the phenylimine rhodium precatalyst and 4 atm of H2 in THF, the manganese nitride (tBuSalen)Mn≡N underwent hydrogenation to liberate free ammonia with up to 6 total turnovers of NH3 or 18 turnovers of H• transfer. The phenylpyridine analogue proved inactive for ammonia synthesis under identical conditions owing to competing deleterious hydride transfer chemistry. Subsequent studies showed that the use of a non-polar solvent such as benzene suppressed formation of the cationic rhodium product resulting from the hydride transfer and enabled catalytic ammonia synthesis by proton-coupled electron transfer.

Relating N-H Bond Strengths to the Overpotential for Catalytic Nitrogen Fixation.

Nitrogen (N2) fixation to produce bio-available ammonia (NH3) is essential to all life but is a challenging transformation to catalyse owing to the chemical inertness of N2. Transition metals can, however, bind N2 and activate it for functionalization. Significant opportunities remain in developing robust and efficient transition metal catalysts for the N2 reduction reaction (N2RR). One opportunity to target in catalyst design concerns the stabilization of transition metal diazenido species (M-NNH) that result from the first N2 functionalization step. Well-characterized M-NNH species remain very rare, likely a consequence of their low N-H bond dissociation free energies (BDFEs). In this essay, we discuss the relationship between the BDFEN-H of a given M-NNH species to the observed overpotential and selectivity for N2RR catalysis with that catalyst system. We note that developing strategies to either increase the N-H BDFEs of M-NNH species, or to avoid M-NNH intermediates altogether, are potential routes to improved N2RR efficiency.

Toward Rational Understandings of α-C-H Functionalization: Energetic Studies of Representative Tertiary Amines.

SummaryFunctionalization of α-C–H bonds of tertiary amines to build various α-C–X bonds has become a mainstream in synthetic chemistry nowadays. However, due to lack of fundamental knowledge on α-C–H bond strength as an energetic guideline, rational exploration of new synthetic methodologies remains a far-reaching anticipation. Herein, we report a unique hydricity-based approach to establish the first integrated energetic scale covering both the homolytic and heterolytic energies of α-C–H bonds for 45 representative tertiary amines and their radical cations. As showcased from the studies on tetrahydroisoquinolines (THIQs) by virtue of their thermodynamic criteria, the feasibility and mechanisms of THIQ oxidation were deduced, which, indeed, were found to correspond well with experimental observations. This integrated scale provides a good example to relate bond energetics with mechanisms and thermodynamic reactivity of amine α-C–H functionalization and hence, may be referenced for analyzing similar structure-property problems for various substrates.

Heme-FeIII Superoxide, Peroxide and Hydroperoxide Thermodynamic Relationships: FeIII-O2•- Complex H-Atom Abstraction Reactivity.

Establishing redox and thermodynamic relationships between metal-ion-bound O2 and its reduced (and protonated) derivatives is critically important for a full understanding of (bio)chemical processes involving dioxygen processing. Here, a ferric heme peroxide complex, [(F8)FeIII-(O22-)]- (P) (F8 = tetrakis(2,6-difluorophenyl)porphyrinate), and a superoxide complex, [(F8)FeIII-(O2•-)] (S), are shown to be redox interconvertible. Using Cr(η-C6H6)2, an equilibrium state where S and P are present is established in tetrahydrofuran (THF) at -80 °C, allowing determination of the reduction potential of S as -1.17 V vs Fc+/0. P could be protonated with 2,6-lutidinium triflate, yielding the low-spin ferric hydroperoxide species, [(F8)FeIII-(OOH)] (HP). Partial conversion of HP back to P using a derivatized phosphazene base gave a P/HP equilibrium mixture, leading to the determination of pKa = 28.8 for HP (THF, -80 °C). With the measured reduction potential and pKa, the O-H bond dissociation free energy (BDFE) of hydroperoxide species HP was calculated to be 73.5 kcal/mol, employing the thermodynamic square scheme and Bordwell relationship. This calculated O-H BDFE of HP, in fact, lines up with an experimental demonstration of the oxidizing ability of S via hydrogen atom transfer (HAT) from TEMPO-H (2,2,6,6-tetramethylpiperdine-N-hydroxide, BDFE = 66.5 kcal/mol in THF), forming the hydroperoxide species HP and TEMPO radical. Kinetic studies carried out with TEMPO-H(D) reveal second-order behavior, kH = 0.5, kD = 0.08 M-1 s-1 (THF, -80 °C); thus, the hydrogen/deuterium kinetic isotope effect (KIE) = 6, consistent with H-atom abstraction by S being the rate-determining step. This appears to be the first case where experimentally derived thermodynamics lead to a ferric heme hydroperoxide OO-H BDFE determination, that FeIII-OOH species being formed via HAT reactivity of the partner ferric heme superoxide complex.

Catalytic generation of alkoxy radicals from unfunctionalized alcohols.

Alkoxy radicals have long been recognized as powerful synthetic intermediates with well-established reactivity patterns. Due to the high bond dissociation free energy of aliphatic alcohol O-H bonds, these radicals are difficult to access through direct homolysis, and conventional methods have instead relied on activation of O-functionalized precursors. Over the past decade, however, numerous catalytic methods for the direct generation of alkoxy radicals from simple alcohol starting materials have emerged and created opportunities for the development of new transformations. This minireview discusses recent advances in catalytic alkoxy radical generation, with particular emphasis on progress toward the direct activation of unfunctionalized alcohols enabled by transition metal and photoredox catalysis.

Ligand stabilized transient “MNC” and its influence on MNC → MCN isomerization process: a computational study (M = Cu, Ag, and Au)

A theoretical investigation of the binding ability of different ligands [L = CO, H2O, H2S, N2, NH3, 1,3-dimethylimidazole (DMI), C2H2 and C2H4] with metal isocyanide and cyanide (MNC and MCN; M = Cu, Ag, Au) compounds has been carried out using quantum chemical computations. In order to analyze the thermochemical stability of these complexes, we have calculated the changes in the related dissociation energies and free energies by considering different possible dissociation pathways (four two-body and one three-body) such as (a) LMCN(/NC) = L + MCN(/NC); (b) LMCN = LM + CN; (c) LMCN = L + M + CN; (d) LMCN = LM+ + CN−; and (e) LMCN = L− + MCN+. The possible dissociation processes are endothermic in nature at room temperature suggesting non-spontaneity at 298 K. Our inspection suggests that MNC have higher binding ability than the MCN compounds in all of the L-bonding cases and both of them follow similar trends as Au > Cu > Ag. The natural bond orbital analysis, topological analysis of the electron density from atoms in molecules technique, and energy decomposition analysis have been carried out to characterize the nature of interaction between L and MCN which shows that the L‐M bonds acquire some degree of covalent character. Furthermore, in order to check the validity of the conceptual DFT-based electronic structure principles like maximum hardness and minimum electrophilicity principles, the change in the relevant global reactivity descriptors like chemical hardness (η), chemical potential (μ), and electrophilicity index (ω) is also studied along the isomerization path, LMNC → LMCN.

Mechanistic Insights into N-Acyloxyamine-Initiated Controlled Degradation of Polypropylene: The Unexpected Role of Keto-Enol Tautomerization in Carboxylate Radical Chemistry.

Controlled degradation of polypropylene (PP) is used industrially to improve the properties of crude PP. While this degradation is traditionally initiated by organic peroxides, N-acyloxyamines are now preferred due to their greater stability. However, their mechanism of action remains unclear. Using high-level ab initio calculations, we show that N-O homolysis is the most likely fragmentation pathway available to N-acyloxyamines, in contrast to the more usual C-O homolysis observed for the closely related N-alkoxyamines. This would, in theory, generate aminyl and carboxylate radicals, with the latter undergoing decarboxylation to generate methyl radicals. However, the enol forms of N-acyloxyamines are significantly less thermally stable, having bond dissociation free energies that are over 50 kJ/mol below those of their keto equivalents. Under conditions where keto-enol tautomerism is feasible, enol N-O homolysis, which forms the more stable acetic acid radical, would be the dominant degradation pathway. This reveals the crucial and underappreciated role that polar impurities play in the initiation process of enolizable initiators and may explain contradictory observations in the experimental literature. The product aminyl radicals are susceptible to β-fragmentation, releasing alkyl radicals and affording imines, which in turn are susceptible to allylic H-abstraction and further β-fragmentation leading to dialkylpyridines as the ultimate degradation products.

Trajectory Taken by Dimeric Cu/Zn Superoxide Dismutase through the Protein Unfolding and Dissociation Landscape Is Modulated by Salt Bridge Formation.

Native mass spectrometry (MS) is a powerful means for studying macromolecular protein assemblies, including accessing activated states. However, much remains to be understood about what governs which regions of the protein (un)folding funnel, which can be explored by activation of protein ions in a vacuum. Here, we examine the trajectory that Cu/Zn superoxide dismutase (SOD1) dimers take over the unfolding and dissociation free energy landscape in a vacuum. We examined wild-type SOD1 and six disease-related point mutants by using tandem MS and ion-mobility MS as a function of collisional activation. For six of the seven SOD1 variants, increasing activation prompted dimers to transition through two unfolding events and dissociate symmetrically into monomers with (as near as possible) equal charges. The exception was G37R, which proceeded only through the first unfolding transition and displayed a much higher abundance of asymmetric products. Supported by the observation that ejected asymmetric G37R monomers were more compact than symmetric G37R ones, we localized this effect to the formation of a gas-phase salt bridge in the first activated conformation. To examine the data quantitatively, we applied Arrhenius-type analysis to estimate the barriers on the corresponding free energy landscape. This reveals a heightening of the barrier to unfolding in G37R by >5 kJ/mol-1 over the other variants, consistent with expectations for the strength of a salt bridge. Our work demonstrates weaknesses in the simple general framework for understanding protein complex dissociation in a vacuum and highlights the importance of individual residues, their local environment, and specific interactions in governing product formation.

Thermal damping of odd-even effects in gold clusters

The amplitude of the odd-even variation in binding energy is calculated for cationic gold clusters, Aun+,n=8-26, extracted from experimental literature data. The data are found to agree fairly well with a simple Fermi gas estimate. Motivated by this, the canonical ensemble free energies are calculated for a ladder spectrum. Experimentally observed differences in ground state dissociation free energies between species with odd and even numbers of valence electrons reach the high temperature limit at temperatures significantly below values corresponding to the HOMO-LUMO gap. Remarkably, the asymptotic high temperature limit does not correspond to the complete disappearance of the zero temperature free energy difference. Likewise, the amount of electronically excited states are significantly higher than a simple estimate based on the Boltzmann factor of the gap energy, having implications for threshold ionization yields.

Thermodynamics of H+/H•/H–/e– Transfer from [CpV(CO)3H]−: Comparisons to the Isoelectronic CpCr(CO)3H

Hydrogen atom (H•) donors generated from H2 facilitate the atom efficient reduction of small molecule substrates. However, generating H• donors with X–H bond dissociation free energies (BDFEs) belo...

Synthesis of Quaternary Carbon-Centered Benzoindolizidinones via Novel Photoredox-Catalyzed Alkene Aminoarylation: Facile Access to Tylophorine and Analogues

Photoredox-catalyzed aminoarylation and thioamination of unactivated alkenes have been developed, providing novel synthetic routes to access synthetically challenging quaternary carbon-centered ben...

Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum.

Autophagy is a degradative pathway associated with many pathological and physiological processes crucial for cell survival. During ER stress, while selective autophagy occurs via ER-phagy, the re-establishment of physiologic ER homeostasis upon resolution of a transient ER stress is mediated by recovER-phagy. Recent studies demonstrated that recovER-phagy is governed via association of Sec62 as an ER-resident autophagy receptor through its autophagy interacting motifs (AIM)/LC3-interacting region (LIR) toAtg8/LC3. Atg8 is an autophagy protein, which is central to autophagosome formation and maturation. Plasmodium falciparum Atg8 (PfAtg8) has both autophagic and non-autophagic functions critical for parasite survival. Since Plasmodium also has Sec62 in the ER membrane and is prone to ER stress due to drastic transformation during their complex intraerythrocytic cycle; hence, we initiated the studies to check whether recovER-phagy occurs in the parasite. To achieve this, a comprehensive study based on the computational approaches was carried out. This study embarks upon identification of AIM sequences in PfSec62 by carrying out peptide-protein docking simulations and comparing the interactions of these AIMs with PfAtg8, based on the molecular dynamic simulations. Detailed analysis is based on electrostatic surface complementarity, peptide-protein interaction strength, mapping of non-covalent bond interactions and rupture force calculated from steered MD simulations. Potential mean forces and unbinding free energies (ΔGdissociation) using Jarzynski's equality were also computed for the AIM/LIR motif complexes with PfAtg8/HsLC3 autophagy proteins to understand their dissociation free energy profiles and thereby their binding affinities and stability of the peptide-protein complexes. Through this study, we predict Sec62 mediated recovER-phagy in Plasmodium falciparum, which might open new avenues to explore novel drug targets for antimalarial drug discovery.