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.
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 N
4 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.
Understanding molecular signaling mechanisms in cells is critically important to biology and medicine. A prominent case is the search for drug targets in cancer signaling pathways. Recently, it was proposed that charge transfer through DNA may enable signaling between iron-sulfur proteins involved in DNA repair and replication. We show that exclusive DNA mediation is energetically unfavorable and kinetically unfeasible, but redox agents might assist the protein signaling. Our analysis narrows the range of possible charge transfer-based mechanisms for intracellular signaling.
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.
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