Correction: Silva, P.J. Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase. 2022, , 779.

In the original publication [...

Discovery of Terpenes as Novel HCV NS5B Polymerase Inhibitors via Molecular Docking.

Hepatitis C virus (HCV) is a dangerous virus that is responsible for a large number of infections and deaths worldwide. In the treatment of HCV, it is important that the drugs are effective and do not have additional hepatotoxic effects. The aim of this study was to test the in silico activity of 1893 terpenes against the HCV NS5B polymerase (PDB-ID: 3FQK).

An Alternative Proposal for the Reaction Mechanism of Light-Dependent Protochlorophyllide Oxidoreductase.

Light-dependent protochlorophyllide oxidoreductase is one of the few known enzymes that require a quantum of light to start their catalytic cycle. Upon excitation, it uses NADPH to reduce the C-C in its substrate (protochlorophyllide) through a complex mechanism that has heretofore eluded precise determination. Isotopic labeling experiments have shown that the hydride-transfer step is very fast, with a small barrier close to 9 kcal mol, and is followed by a proton-transfer step, which has been postulated to be the protonation of the product by the strictly conserved Tyr189 residue.

Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase.

Resistance to trimethoprim and other antibiotics targeting dihydrofolate reductase may arise in bacteria harboring an atypical, plasmid-encoded, homotetrameric dihydrofolate reductase, called R67 DHFR. Although developing inhibitors to this enzyme may be expected to be promising drugs to fight trimethoprim-resistant strains, there is a paucity of reports describing the development of such molecules. In this manuscript, we describe the design of promising lead compounds to target R67 DHFR.

Response to "Molecular-level understanding of biological energy coupling and transduction: Response to "Chemiosmotic misunderstandings"".

The most recent contribution by Sunil Nath in these pages is, mostly, a repetition of his previous claims regarding failures of the chemiosmotic hypotheses, supplemented with some fresh misunderstandings of the points I had sought to clarify in my previous critique⁠. Considerable portions rehash 50-60 years-old controversies, with no apparent understanding that the current chemiosmotic hypothesis, while birthed by Mitchell, differs from Mitchell's details in many respects. As such, Nath has devoted much time dealing with a few errors (or wrong hypotheses) by Mitchell (in a few places I would almost venture to say "typographical mistakes in typesetting") and presents the ensuing conclusions as "refutations" of the chemiosmotic paradigm, completely neglecting that such details (such as the precise H/ATP or H:O ratios) are completely irrelevant to the reality (or not) of an electron-transport chain that uses the free energy liberated by electron-transfer to remove H from a compartment, to which it returns through and ATP synthase which uses the energy in that spontaneous return to drive ATP synthesis.

Chemiosmotic misunderstandings.

Recent publications have questioned the appropriateness of the chemiosmotic theory, a key tenet of modern bioenergetics originally described by Mitchell and since widely improved upon and applied. In one of them, application of Gauss' law to a model charge distribution in mitochondria was argued to refute the possibility of ATP generation through H movement in the absence of a counterion, whereas a different author advocated, for other reasons, the impossibility of chemiosmosis and proposed that a novel energy-generation scheme (referred to as "murburn") relying on superoxide-catalyzed (or superoxide-promoted) ADP phosphorylation would operate instead. In this letter, those proposals are critically examined and found to be inconsistent with established experimental data and new theoretical calculations.

Computational improvement of small-molecule inhibitors of protective antigen activation through isostere-based substitutions.

There has recently been interest in the development of small-molecule inhibitors of the oligomerization of protective antigen for therapeutic use. Some of the proposed lead compounds have, however, unfavorable solubility in aqueous medium, which prevents their clinical use. In this computational work, we have designed several hundreds of derivatives with progressively higher hydro-solubility and tested their ability to dock the relevant binding cavity.

Influence of Alkyne and Azide Substituents on the Choice of the Reaction Mechanism of the Cu-Catalyzed Addition of Azides to Iodoalkynes.

The cycloaddition of azides to iodoalkynes is strongly enhanced by some Cu-complexes. We have studied computationally six reaction pathways for the cycloaddition of 24 combinations of azide and iodoalkyne to identify the dominant pathways and the influence of reactant structure on the evolution of the reaction. Two pathways were found to be operating for distinct sets of reactants.

Refining the reaction mechanism of O towards its co-substrate in cofactor-free dioxygenases.

Cofactor-less oxygenases perform challenging catalytic reactions between singlet co-substrates and triplet oxygen, in spite of apparently violating the spin-conservation rule. In 1--3-hydroxy-4-oxoquinaldine-2,4-dioxygenase, the active site has been suggested by quantum chemical computations to fine tune triplet oxygen reactivity, allowing it to interact rapidly with its singlet substrate without the need for spin inversion, and in urate oxidase the reaction is thought to proceed through electron transfer from the deprotonated substrate to an aminoacid sidechain, which then feeds the electron to the oxygen molecule. In this work, we perform additional quantum chemical computations on these two systems to elucidate several intriguing features unaddressed by previous workers.

Will 1,2-dihydro-1,2-azaborine-based drugs resist metabolism by cytochrome P450 compound I?

1,2-dihydro-1,2-azaborine is a structural and electronic analogue of benzene which is able to occupy benzene-binding pockets in T4 lysozyme and has been proposed as suitable arene-mimicking group for biological and pharmaceutical applications. Its applicability in a biological context requires it to be able to resist modification by xenobiotic-degrading enzymes like the P450 cytochromes. Quantum chemical computations described in this work show that 1,2-dihydro-1,2-azaborine is much more prone to modification by these enzymes than benzene, unless steric crowding of the ring prevents it from reaching the active site, or otherwise only allows reaction at the less reactive C4-position.

Computational exploration of the reaction mechanism of the Cu(+)-catalysed synthesis of indoles from N-aryl enaminones.

We have studied the role of Cu(+)-phenantroline as a catalyst in the cyclization of N-aryl-enaminones using density-functional theory computations. The catalyst was found to bind the substrate upon deprotonation of its eneaminone, and to dramatically increase the acidity of the carbon adjacent to the ketone functionality. The deprotonation of this carbon atom yields a carbanion which attacks the aryl moiety, thereby closing the heterocycle in the rate-determining step.

Mechanistic pathways of mercury removal from the organomercurial lyase active site.

Bacterial populations present in Hg-rich environments have evolved biological mechanisms to detoxify methylmercury and other organometallic mercury compounds. The most common resistance mechanism relies on the H(+)-assisted cleavage of the Hg-C bond of methylmercury by the organomercurial lyase MerB. Although the initial reaction steps which lead to the loss of methane from methylmercury have already been studied experimentally and computationally, the reaction steps leading to the removal of Hg(2+) from MerB and regeneration of the active site for a new round of catalysis have not yet been elucidated.

With or without light: comparing the reaction mechanism of dark-operative protochlorophyllide oxidoreductase with the energetic requirements of the light-dependent protochlorophyllide oxidoreductase.

The addition of two electrons and two protons to the C17=C18 bond in protochlorophyllide is catalyzed by a light-dependent enzyme relying on NADPH as electron donor, and by a light-independent enzyme bearing a (Cys)3Asp-ligated [4Fe-4S] cluster which is reduced by cytoplasmic electron donors in an ATP-dependent manner and then functions as electron donor to protochlorophyllide. The precise sequence of events occurring at the C17=C18 bond has not, however, been determined experimentally in the dark-operating enzyme. In this paper, we present the computational investigation of the reaction mechanism of this enzyme at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory.

Computational development of rubromycin-based lead compounds for HIV-1 reverse transcriptase inhibition.

The binding of several rubromycin-based ligands to HIV1-reverse transcriptase was analyzed using molecular docking and molecular dynamics simulations. MM-PBSA analysis and examination of the trajectories allowed the identification of several promising compounds with predicted high affinity towards reverse transcriptase mutants which have proven resistant to current drugs. Important insights on the complex interplay of factors determining the ability of ligands to selectively target each mutant have been obtained.

Evaluation of density functional methods on the geometric and energetic descriptions of species involved in Cu⁺-promoted catalysis.

We have evaluated the performance of 15 density functionals of diverse complexity on the geometry optimization and energetic evaluation of model reaction steps present in the proposed reaction mechanisms of Cu(I)-catalyzed indole synthesis and click chemistry of iodoalkynes and azides. The relative effect of the Cu(+) ligand on the relative strength of Cu(+)-alkyne interactions, and the strong preference for a π-bonding mode is captured by all functionals. The best energetic correlations with MP2 are obtained with PBE0, M06-L, and PBE1PW91, which also provide good quality geometries.

Unravelling the reaction mechanism of the reductive ring contraction of 1,2-pyridazines.

Substituted pyrroles may be synthesized from selected 1,2-pyridazines through a reductive ring contraction involving the addition of four electrons and four protons. Our density functional theory computations of this reaction mechanism show that the first reduction event must be preceded by the uptake of one proton by 1,2-pyridazine and that the reaction proceeds through a 2e(-)/3H(+)-bearing intermediate. In the absence of electron-withdrawing groups able to resonate charge away from the ring, this intermediate lies too high in energy, making the reaction sequence thermodynamically inaccessible.

Flux periodicities and quantum hair on holographic superconductors.

Superconductors in a cylindrical geometry respond periodically to a cylinder-threading magnetic flux, with the period changing from hc/2e to hc/e depending on whether the Aharonov-Bohm effects are suppressed. We show that holographic superconductors present a similar phenomenon, and that the different periodicities follow from classical no-hair theorems. We also give the Ginzburg-Landau description of the period-doubling phenomenon.

Computational characterization of the substrate-binding mode in coproporphyrinogen III oxidase.

Oxygen-dependent coproporphyrinogen III oxidase catalyzes the sequential decarboxylation of the propionate substituents present on the A and B rings of coproporphyrinogen III in the heme biosynthetic pathway. Although extensive experimental investigation of this enzyme has already afforded many insights into its reaction mechanism, several key features (such as the substrate binding mode, the characterization of the active site, and the initial substrate protonation state) remain poorly described. The molecular dynamics simulations described in this paper enabled the determination of a very promising substrate binding mode and the extensive characterization of the enzyme active site.

A tale of two acids: when arginine is a more appropriate acid than H3O+.

Uroporphyrinogen III decarboxylase catalyzes the fifth step in heme biosynthesis, the elimination of carboxyl groups from the four acetate side chains of uroporphyrinogen III to yield coproporphyrinogen III. We have previously found that the rate-limiting step of uroporphyrinogen III decarboxylase is substrate protonation rather than the decarboxylation reaction. This protonation can be effected by an arginine residue (Arg37) in close proximity to the substrate.

Holographic superconductor vortices.

A gravity dual of a superconductor at finite temperature has been recently proposed. We present the vortex configuration of this model and study its properties. In particular, we calculate the free energy as a function of an external magnetic field, the magnetization, and the superconducting density.

Computational studies on the reactivity of substituted 1,2-dihydro-1,2-azaborines.

We have investigated important intermediates of electrophilic aromatic substitution reactions and one-electron oxidation of substituted 1,2-dihydro-1,2-azaborines with density-functional theory. The results show that electrophilic substitution reactions and one-electron oxidation of substituted 1,2-azaborines are generally much more favorable than those of the corresponding benzene derivatives. Both chlorination and nitration of several boron-unsubstituted 1,2-azaborines are expected to break the boron-hydrogen bond, yielding boron-chlorinated 1,2-azaborines and a novel class of boron-bound 1,2-azaborinyl nitrites, respectively.

Inductive and resonance effects on the acidities of phenol, enols, and carbonyl alpha-hydrogens.

Inductive effects account for 1/3 of the enhanced acidity of phenol versus cyclohexanol, 2/5 of the enhanced acidity of enol versus methanol, and l/4 of the enhanced acidity of carbonyl alpha-hydrogens versus methane.

Comparative density functional study of models for the reaction mechanism of uroporphyrinogen III synthase.

The asymmetric cyclic tetrapyrrole uroporphyrinogen III is the common precursor of heme, chlorophyll, siroheme, and other biological tetrapyrroles. In vivo, it is synthesized from a linear symmetric precursor (hydroxymethylbilane) by uroporphyrinogen III synthase, which catalyzes the inversion of one of the four heterocyclic rings present in the substrate. Two mechanisms have been proposed to explain this puzzling ring inversion, either through sigmatropic shifts or through the direct formation of a spirocyclic pyrrolenine intermediate.

A comparative density-functional study of the reaction mechanism of the O2-dependent coproporphyrinogen III oxidase.

During heme biosynthesis, coproporphyrinogen III oxidase catalyzes the conversion of two propionate substituents from the highly reactive substrate coproporphyrinogen III into vinyl substituents, yielding protoporphyrinogen IX. Although the crystal structure of this important enzyme has recently been reported, the reaction mechanism of this intriguing enzyme remains the subject of intense speculation, as impairment of this enzyme has been shown to be the molecular cause behind hereditary coproporphyria. We have performed DFT calculations on model systems in order to analyze several reaction mechanisms proposed for this enzyme.