Elucidation of factors shaping reactivity of 5'-deoxyadenosyl - a prominent organic radical in biology.

This study investigates the factors modulating the reactivity of 5'-deoxyadenosyl (5'dAdo˙) radical, a potent hydrogen atom abstractor that forms in the active sites of radical SAM enzymes and that otherwise undergoes a rapid self-decay in aqueous solution. Here, we compare hydrogen atom abstraction (HAA) reactions between native substrates of radical SAM enzymes and 5'dAdo˙ in aqueous solution and in two enzymatic microenvironments. With that we reveal that HAA efficiency of 5'dAdo˙ is due to (i) the in situ formation of 5'dAdo˙ in a pre-ordered complex with a substrate, which attenuates the unfavorable effect of substrate:5'dAdo˙ complex formation, and (ii) the prevention of the conformational changes associated with self-decay by a tight active-site cavity. The enzymatic cavity, however, does not have a strong effect on the HAA activity of 5'dAdo˙. Thus, we performed an analysis of in-water HAA performed by 5'dAdo˙ based on a three-component thermodynamic model incorporating the diagonal effect of the free energy of reaction, and the off-diagonal effect of asynchronicity and frustration. To this aim, we took advantage of the straightforward relationship between the off-diagonal thermodynamic effects and the electronic-structure descriptor - the redistribution of charge between the reactants during the reaction. It allows to access HAA-competent redox and acidobasic properties of 5'dAdo˙ that are otherwise unavailable due to its instability upon one-electron reduction and protonation. The results show that all reactions feature a favourable thermodynamic driving force and tunneling, the latter of which lowers systematically barriers by ∼2 kcal mol-1. In addition, most of the reactions experience a favourable off-diagonal thermodynamic contribution. In HAA reactions, 5'dAdo˙ acts as a weak oxidant as well as a base, also 5'dAdo˙-promoted HAA reactions proceed with a quite low degree of asynchronicity of proton and electron transfer. Finally, the study elucidates the crucial and dual role of asynchronicity. It directly lowers the barrier as a part of the off-diagonal thermodynamic contribution, but also indirectly increases the non-thermodynamic part of the barrier by presumably controlling the adiabatic coupling between proton and electron transfer. The latter signals that the reaction proceeds as a hydrogen atom transfer rather than a proton-coupled electron transfer.

Computational investigation on the effect of the peptidomimetic inhibitors (NPT100-18A and NPT200-11) on the α-synuclein and lipid membrane interactions.

Parkinson's disease (PD) is associated with α-synuclein (α-Syn), a presynaptic protein that binds to cell membranes. The molecular pathophysiology of PD most likely begins with the binding of α-Syn to membranes. Recently, two peptidomimetic inhibitors (NPT100-18A and NPT200-11) were identified to potentially interact with α-Syn and affect the interaction of α-Syn with the membrane. In this study, the effect of the two peptidomimetic inhibitors on the α-Syn-membrane interaction was demonstrated. DFT calculations were performed for optimization of the two inhibitors, and the nucleophilicity (N) and electrophilicity (ω) of NPT100-18A and NPT200-11 were calculated to be 3.90 and 3.86 (N); 1.06 and 1.04 (ω), respectively. Using the docking tool (CB-dock2), the two α-Syn-peptidomimetic inhibitor complexes (α-Syn-NPT100-18A and α-Syn-NPT200-11) have been prepared. Then all-atom molecular dynamics (MD) simulation was carried out on the α-Syn (control), α-Syn-NPT100-18A and α-Syn-NPT200-11 complex systems in presence of DOPE: DOPS: DOPC (5:3:2) lipid bilayer. From the conformational dynamics analysis, the 3-D structure of α-Syn was found to be stable, and the helices present in the regions (1-37) and (45-95) of α-Syn were found to be retained in the presence of the two peptidomimetic inhibitors. The electron density profile analysis revealed the binding modes of NAC and C-terminal region of α-Syn (in the presence of NPT200-11 inhibitor) with lipid membrane are in the close vicinity from the lipid bilayer centre. Our findings in this study on α-Syn-membrane interactions may be useful for developing a new therapeutic approach for treating PD and other neurodegenerative disorders.Communicated by Ramaswamy H. Sarma.

Reactivity Factors in Catalytic Methanogenesis and Their Tuning upon Coenzyme F430 Biosynthesis.

Methyl-coenzyme M reductase, responsible for the biological production of methane by catalyzing the reaction between coenzymes B (CoBS-H) and M (H3C-SCoM), hosts in its core an F430 cofactor with the low-valent NiI ion. The critical methanogenic step involves F430-assisted reductive cleavage of the H3C-S bond in coenzyme M, yielding the transient CH3 radical capable of hydrogen atom abstraction from the S-H bond in coenzyme B. Here, we computationally explored whether and why F430 is unique for methanogenesis in comparison to four identified precursors formed consecutively during its biosynthesis. Indeed, all precursors are less proficient than the native F430, and catalytic competence improves at each biosynthetic step toward F430. Against the expectation that F430 is tuned to be the strongest possible reductant to expedite the rate-determining reductive cleavage of H3C-S by NiI, we discovered the opposite. The unfavorable increase in reduction potential along the F430 biosynthetic pathway is outweighed by strengthening of the Ni-S bond formed upon reductive cleavage of the H3C-S bond. We found that F430 is the weakest electron donor, compared to its precursors, giving rise to the most covalent Ni-S bond, which stabilizes the transition state and hence reduces the rate-determining barrier. In addition, the transition state displays high pro-reactive motion of the transient CH3 fragment toward the H-S bond, superior to its biosynthetic ancestors and likely preventing the formation of a deleterious radical intermediate. Thus, we show a plausible view of how the evolutionary driving force shaped the biocatalytic proficiency of F430 toward CH4 formation.

Bifurcating reactions: distribution of products from energy distribution in a shared reactive mode.

Bifurcating reactions yield two different products emerging from one single transition state and are therefore archetypal examples of reactions that cannot be described within the framework of the traditional Eyring's transition state theory (TST). With the growing number and importance of these reactions in organic and biosynthetic chemistry, there is also an increasing demand for a theoretical tool that would allow for the accurate quantification of reaction outcome at low cost. Here, we introduce such an approach that fulfils these criteria, by evaluating bifurcation selectivity through the energy distribution within the reactive mode of the key transition state. The presented method yields an excellent agreement with experimentally reported product ratios and predicts the correct selectivity for 89% of nearly 50 various cases, covering pericyclic reactions, rearrangements, fragmentations and metal-catalyzed processes as well as a series of trifurcating reactions. With 71% of product ratios determined within the error of less than 20%, we also found that the methodology outperforms three other tested protocols introduced recently in the literature. Given its predictive power, the procedure makes reaction design feasible even in the presence of complex non-TST chemical steps.

Activation of small molecules by cyclic alkyl amino silylenes (CAASis) and germylenes (CAAGes): a theoretical study.

Quantum chemical calculations have been carried out on a series of skeletally modified cyclic alkyl amino silylenes (CAASis) and germylenes (CAAGes) to understand their ligand properties and reactivity towards the activation of a variety of small molecules. The installation of boron or silicon atoms into the ring framework of these silylenes/germylenes led to a dramatic increase in their σ-basicity while the incorporation of ylidic moieties resulted in a sharp reduction of their π-acidity although it did help in increasing the electron donation ability. The calculated values of energy barriers for the activation of H-H, N-H, C-H and Si-H bonds by many of the cyclic silylenes considered here are found to be comparable to those for experimentally evaluated systems, indicating the potential of these computationally designed molecules in small molecule activation and calling for synthetic efforts towards their isolation. Furthermore, activations employing CAAGes are found to be more demanding than those with CAASis which may be attributed to the significantly lower Lewis basicity of the former than the latter.

Introducing N-Heterocyclic Borylenes: Theoretical Prediction of Stable, Neutral, Monomeric Boron(I) Carbenoids.

Quantum-chemical calculations predict that synthetically accessible cyclic four-membered, four-π-electron ylides could be used as building blocks for the realization of hitherto unknown N-heterocyclic boron(I) carbenoids. The boron(I) carbenoids proposed in this work possess the largest computed singlet-triplet separations known to date, which are comparable to those of the corresponding aluminum(I) analogue computed at the same level of theory. Furthermore, they owe their stability not only to the substantial transfer of electron density from nitrogen to boron atoms but also to the presence of thermodynamically robust ylidic bonds. On the basis of their computed proton affinity and carbonyl stretching frequencies, they may be considered as promising ligands for transition-metal complexes.

Electronic and Ligand Properties of Skeletally Substituted Cyclic (Alkyl)(Amino)Carbenes (CAACs) and Their Reactivity towards Small Molecule Activation: A Theoretical Study.

Quantum chemical calculations have been carried out to understand the ligand properties of skeletally modified cyclic alkyl amino carbenes. The stability of these carbenes has been assessed from an evaluation of their singlet-triplet and stabilization energy values. Ylide substituted carbenes are found to be more stable than non-ylidic ones in their optimized singlet state. Nucleophilicity and electrophilicity indices values were evaluated in order to further investigate the reactivity of these carbenes. The calculated values of proton affinities and the degree of gallium pyramidalization in the carbene-GaCl3 adducts correlate well with the σ-basicity of these carbenes. The reactivity of non-ylidic carbenes toward the activation of both H2 and NH3 are calculated to be more favourable compared to that of parent CAAC. On the other hand, ylide anchored carbenes are found to be unsuccessful toward the activation of both H2 and NH3 .

Annulated boron substituted N-heterocyclic carbenes: theoretical prediction of highly electrophilic carbenes.

Theoretical calculations were carried out to understand the effect of annulation on the electronic and ligand properties of boron substituted N-heterocyclic carbenes (B-NHCs). Annulation results in a decrease in stability as indicated by the calculated values of singlet-triplet separations and stabilization energies as well as HOMO-LUMO gaps. Annulated B-NHCs are found to be weaker σ-donors but better π-acceptors than the parent ones. The decrease in σ-donation ability and the increase in π-accepting ability are further supported by the calculated values of proton affinities, nucleophilicity and electrophilicity indices as well as (31)P NMR chemical shifts of the corresponding NHC-PPh adducts. Most of the annulated B-NHCs are found to have significantly enhanced electrophilicity than the other known carbenes.