Computational Insights into the Mechanism of Nitric Oxide Generation from S-Nitrosoglutathione Catalyzed by a Copper Metal-Organic Framework.

The controlled generation of nitric oxide (NO) from endogenous sources, such as S-nitrosoglutathione (GSNO), has significant implications for biomedical implants due to the vasodilatory and other beneficial properties of NO. The water-stable metal-organic framework (MOF) Cu-1,3,5-tris[1H-1,2,3-triazol-5-yl]benzene has been shown to catalyze the production of NO and glutathione disulfide (GSSG) from GSNO in aqueous solution as well as in blood. Previous experimental work provided kinetic data for the catalysis of the 2GSNO → 2NO + GSSG reaction, leading to various proposed mechanisms. Herein, this catalytic process is examined using density functional theory. Minimal functional models of the Cu-MOF cluster and glutathione moieties are established, and three distinct catalytic mechanisms are explored. The most thermodynamically favorable mechanism studied is consistent with prior experimental findings. This mechanism involves coordination of GSNO to copper via sulfur rather than nitrogen and requires a reductive elimination that produces a Cu(I) intermediate, implicating a redox-active copper site. The experimentally observed inhibition of reactivity at high pH values is explained in terms of deprotonation of a triazole linker, which decreases the structural stability of the Cu(I) intermediate. These fundamental mechanistic insights may be generally applicable to other MOF catalysts for NO generation.

Adenine Fine-Tunes DNA Photolyase's Repair Mechanism.

The comparative study of DNA repair by mesophilic and extremophilic photolyases helps us understand the evolution of these enzymes and their role in preserving life on our changing planet. The mechanism of repair of cyclobutane pyrimidine dimer lesions in DNA by electron transfer from the flavin adenine dinucleotide cofactor is the subject of intense interest. The role of adenine in mediating this process remains unresolved. Using microsecond molecular dynamics simulations, we find that adenine mediates the electron transfer in both mesophile and extremophile DNA photolyases through a similar mechanism. In fact, in all photolyases studied, the molecular conformations with the largest electronic couplings between the enzyme cofactor and DNA show the presence of adenine in 10-20% of the strongest-coupling tunneling pathways between the atoms of the electron donor and acceptor. Our theoretical analysis finds that adenine serves the critical role of fine-tuning rather than maximizing the donor-acceptor coupling within the range appropriate for the repair function.

Multicomponent Orbital-Optimized Perturbation Theory Methods: Approaching Coupled Cluster Accuracy at Lower Cost.

Multicomponent quantum chemistry methods such as the nuclear-electronic orbital (NEO) method allow the consistent quantum mechanical treatment of electrons and nuclei. The development of computationally practical, accurate, and robust multicomponent wave function methods is challenging because of the importance of orbital relaxation effects. Herein the variational orbital-optimized coupled cluster with doubles (NEO-OOCCD) method and the orbital-optimized second-order Møller-Plesset perturbation theory (NEO-OOMP2) method with scaled-opposite-spin (SOS) versions are developed and applied to molecular systems in which a proton and all electrons are treated quantum mechanically. The results highlight the importance of orbital relaxation in multicomponent wave function methods. The NEO-SOS'-OOMP2 method, which scales the electron-proton correlation energy as well as the opposite-spin and same-spin components of the electronic correlation energy, is found to achieve nearly the same level of accuracy as the NEO-OOCCD method for proton densities, proton affinities, and optimized geometries. An advantage of the NEO-SOS'-OOMP2 method is that it can be implemented with N4 scaling, where N is a measure of the system size. This method will enable future multicomponent wave function calculations of structures, energies, reaction paths, and dynamics for substantially larger chemical systems.

Correction: Charge Transfer between [4Fe4S] Proteins and DNA Is Unidirectional: Implications for Biomolecular Signaling.

[This corrects the article PMC6350243.].

Charge Transfer between [4Fe4S] Proteins and DNA Is Unidirectional: Implications for Biomolecular Signaling.

Recent experiments suggest that DNA-mediated charge transport might enable signaling between the [4Fe4S] clusters in the C-terminal domains of human DNA primase and polymerase α, as well as the signaling between other replication and repair high-potential [4Fe4S] proteins. Our theoretical study demonstrates that the redox signaling cannot be accomplished exclusively by DNA-mediated charge transport because part of the charge transfer chain has an unfavorable free energy profile. We show that hole or excess electron transfer between a [4Fe4S] cluster and a nucleic acid duplex through a protein medium can occur within microseconds in one direction, while it is kinetically hindered in the opposite direction. We present a set of signaling mechanisms that may occur with the assistance of oxidants or reductants, using the allowed charge transfer processes. These mechanisms would enable the coordinated action of [4Fe4S] proteins on DNA, engaging the [4Fe4S] oxidation state dependence of the protein-DNA binding affinity.

Determinants of Photolyase's DNA Repair Mechanism in Mesophiles and Extremophiles.

Light-driven DNA repair by extremophilic photolyases is of tremendous importance for understanding the early development of life on Earth. The mechanism for flavin adenine dinucleotide repair of DNA lesions is the subject of debate and has been studied mainly in mesophilic species. In particular, the role of adenine in the repair process is poorly understood. Using molecular docking, molecular dynamics simulations, electronic structure calculations, and electron tunneling pathways analysis, we examined adenine's role in DNA repair in four photolyases that thrive at different temperatures. Our results indicate that the contribution of adenine to the electronic coupling between the flavin and the cyclobutane pyrimidine dimer lesion to be repaired is significant in three (one mesophilic and two extremophilic) of the four enzymes studied. Our analysis suggests that thermophilic and hyperthermophilic photolyases have evolved structurally to preserve the functional position (and thus the catalytic function) of adenine at their high temperatures of operation. Water molecules can compete with adenine in establishing the strongest coupling pathway for the electron transfer repair process, but the adenine contribution remains substantial. The present study also reconciles prior seemingly contradictory conclusions on the role of adenine in mesophile electron transfer repair reactions, showing how adenine-mediated superexchange is conformationally gated.