Copper(II) coordination to the intrinsically disordered region of SARS-CoV-2 Nsp1.

The intrinsically disordered C-terminal peptide region of severe acute respiratory syndrome coronavirus 2 nonstructural protein-1 (Nsp1-CT) inhibits host protein synthesis by blocking messenger RNA (mRNA) access to the 40S ribosome entrance tunnel. Aqueous copper(II) ions bind to the disordered peptide with micromolar affinity, creating a possible strategy to restore protein synthesis during host infection. Electron paramagnetic resonance (EPR) and tryptophan fluorescence measurements on a 10-residue model of the disordered protein region (Nsp1-CT), combined with advanced quantum mechanics calculations, suggest that the peptide binds to copper(II) as a multidentate ligand.

Tryptophan to Tryptophan Hole Hopping in an Azurin Construct.

Electron transfer (ET) between neutral and cationic tryptophan residues in the azurin construct [Re(H126)(CO)(dmp)](W124)(W122)Cu (dmp = 4,7-Me-1,10-phenanthroline) was investigated by Born-Oppenheimer quantum-mechanics/molecular mechanics/molecular dynamics (QM/MM/MD) simulations. We focused on W124 ← W122 ET, which is the middle step of the photochemical hole-hopping process *Re(CO)(dmp) ← W124 ← W122 ← Cu, where sequential hopping amounts to nearly 10,000-fold acceleration over single-step tunneling (. , , 192-200).

Tryptophan extends the life of cytochrome P450.

Powerfully oxidizing enzymes need protective mechanisms to prevent self-destruction. The flavocytochrome P450 BM3 from (P450) is a self-sufficient monooxygenase that hydroxylates fatty acid substrates using O and NADPH as co-substrates. Hydroxylation of long-chain fatty acids (≥C) is well coupled to O and NADPH consumption, but shorter chains (≤C) are more poorly coupled.

Reversible Reactions of Nitric Oxide with a Binuclear Iron(III) Nitrophorin Mimic.

Construction of functional synthetic systems that can reversibly bind and transport the most biologically important gaseous molecules, oxygen and nitric oxide (NO), remains a contemporary challenge. Myoglobin and nitrophorin perform these respective tasks employing a protein-embedded heme center where one axial iron site is occupied by a histidine residue and the other is available for small molecule ligation, structural features that are extremely difficult to mimic in protein-free environments. Indeed, the hitherto reported designs rely on sophisticated multistep syntheses for limiting access to one of the two axial coordination sites in small molecules.

Resonance Raman spectra of blue copper proteins: Variable temperature spectra of Thermus thermophilus HB27 laccase.

The resonance Raman (rR) spectra of the oxidized type 1 copper active site (Cu) in Thermus thermophilus HB27 laccase (Tth-lac) has been determined in the 20 to 80 °C temperature range using 633-nm excitation. The positions and relative intensities of rR peaks are virtually independent of temperature, indicating that Cu ligation is robust over the investigated range. The intensity-weighted average of Tth-lac Cu-S vibrations (<ν(Cu-S)>) = 423 cm) is higher than those of most cupredoxins but is comparable to those of other multicopper oxidases (MCOs).

Electronic Structures and Photoredox Chemistry of Tungsten(0) Arylisocyanides.

ConspectusThe high energy barriers associated with the reaction chemistry of inert substrates can be overcome by employing redox-active photocatalysts. Research in this area has grown exponentially over the past decade, as transition metal photosensitizers have been shown to mediate challenging organic transformations. Critical for the advancement of photoredox catalysis is the discovery, development, and study of complexes based on earth-abundant metals that can replace and/or complement established noble-metal-based photosensitizers.

Boronated Cyanometallates.

Thirteen boronated cyanometallates [M(CN-BR)] [M = Cr, Mn, Fe, Ru, Os; BR = BPh, B(2,4,6,-FCH), B(CF)] and one metalloboratonitrile [Cr(NC-BPh)] have been characterized by X-ray crystallography and spectroscopy [UV-vis-near-IR, NMR, IR, spectroelectrochemistry, and magnetic circular dichroism (MCD)]; CASSCF+NEVPT2 methods were employed in calculations of electronic structures. For (t) electronic configurations, the lowest-energy ligand-to-metal charge-transfer (LMCT) absorptions and MCD -terms in the spectra of boronated species have been assigned to transitions from cyanide π + B-C borane σ orbitals. CASSCF+NEVPT2 calculations including t and t orbitals reproduced t/t → t excitation energies.

Tryptophan-96 in cytochrome P450 BM3 plays a key role in enzyme survival.

Flavocytochrome P450 from Bacillus megaterium (P450 ) is a natural fusion protein containing reductase and heme domains. In the presence of NADPH and dioxygen the enzyme catalyses the hydroxylation of long-chain fatty acids. Analysis of the P450 structure reveals chains of closely spaced tryptophan and tyrosine residues that might serve as pathways for high-potential oxidizing equivalents to escape from the heme active site when substrate oxidation is not possible.

Does Tyrosine Protect Laccase from Oxidative Degradation or Act as an Extended Catalytic Site?

We have investigated the roles of tyrosine (Tyr) and tryptophan (Trp) residues in the four-electron reduction of oxygen catalyzed by laccase (SLAC). During normal enzymatic turnover in laccases, reducing equivalents are delivered to a type 1 Cu center (Cu) and then are transferred over 13 Å to a trinuclear Cu site (TNC: (Cu)Cu) where O reduction occurs. The TNC in SLAC is surrounded by a large cluster of Tyr and Trp residues that can provide reducing equivalents when the normal flow of electrons is disrupted.

Control of protein activity by photoinduced spin polarized charge reorganization.

Considerable electric fields are present within living cells, and the role of bioelectricity has been well established at the organismal level. Yet much remains to be learned about electric-field effects on protein function. Here, we use phototriggered charge injection from a site-specifically attached ruthenium photosensitizer to directly demonstrate the effect of dynamic charge redistribution within a protein.

Surface cysteines could protect the SARS-CoV-2 main protease from oxidative damage.

The SARS-CoV-2 main protease (M) is responsible for cleaving twelve nonstructural proteins from the viral polyprotein. M, a cysteine protease, is characterized by a large number of noncatalytic cysteine (Cys) residues, none involved in disulfide bonds. In the absence of a tertiary-structure stabilizing role for these residues, a possible alternative is that they are involved in redox processes.

Copper(II) Binding to the Intrinsically Disordered C-Terminal Peptide of SARS-CoV-2 Virulence Factor Nsp1.

The first encoded SARS-CoV-2 protein (Nsp1) binds to the human 40S ribosome and blocks synthesis of host proteins, thereby inhibiting critical elements of the innate immune response. The final 33 residues of the natively unstructured Nsp1 C-terminus adopt a helix-turn-helix geometry upon binding to the ribosome. We have characterized the fluctuating conformations of this peptide using circular dichroism spectroscopy along with measurements of tryptophan fluorescence and energy transfer.

Photoredox Catalysis Mediated by Tungsten(0) Arylisocyanides in 1,2-Difluorobenzene.

We have studied the photochemical cyclization of 1-(2-iodobenzyl)-pyrrole (IBP) and 1-(2-bromobenzyl)-pyrrole (BBP) to 5-pyrrolo[2,1-]isoindol catalyzed by W(CNDipp) (CNDipp = 2,6-diisopropylphenylisocyanide) in 1,2-difluorobenzene (DFB). Irradiation (445 nm) of W(CNDipp) (5 mol %) in DFB solution converted 78% of IBP (50 mM) to product after 1 h (16 turnovers). Addition of tetra--butyl ammonium hexafluorophosphate (TBAPF) (0.

Longitudinal manganese-enhanced magnetic resonance imaging of neural projections and activity.

Manganese-enhanced magnetic resonance imaging (MEMRI) holds exceptional promise for preclinical studies of brain-wide physiology in awake-behaving animals. The objectives of this review are to update the current information regarding MEMRI and to inform new investigators as to its potential. Mn(II) is a powerful contrast agent for two main reasons: (1) high signal intensity at low doses; and (2) biological interactions, such as projection tracing and neural activity mapping via entry into electrically active neurons in the living brain.

Frustration Dynamics and Electron-Transfer Reorganization Energies in Wild-Type and Mutant Azurins.

Long-range electron tunneling through metalloproteins is facilitated by evolutionary tuning of donor-acceptor electronic couplings, formal electrochemical potentials, and active-site reorganization energies. Although the minimal frustration of the folding landscape enables this tuning, residual frustration in the vicinity of the metallocofactor can allow conformational fluctuations required for protein function. We show here that the constrained copper site in wild-type azurin is governed by an intricate pattern of minimally frustrated local and distant interactions that together enable rapid electron flow to and from the protein.

Excitation-Wavelength-Dependent Photophysics of dd Di-isocyanide Complexes.

Binuclear Rh(I) and Ir(I) TMB (2,5-dimethyl-2,5-diisocyanohexane) and dimen (1,8-diisocyanomenthane) complexes possess dσ*pσ and dπpσ singlet and triplet excited states that can be selectively excited in the visible and UV spectral regions. Using perturbational spin-orbit TDDFT, we unraveled the detailed character and spin mixing of these electronic transitions and found that delocalization of pσ and dπ orbitals over C≡N- groups makes C≡N stretching vibrations sensitive reporters of electron density and structural changes upon electronic excitation. Picosecond time-resolved infrared spectra measured after visible light, 375 nm, and 316 nm excitation revealed excitation-wavelength-dependent deactivation cascades.

Functional and protective hole hopping in metalloenzymes.

Electrons can tunnel through proteins in microseconds with a modest release of free energy over distances in the 15 to 20 Å range. To span greater distances, or to move faster, multiple charge transfers (hops) are required. When one of the reactants is a strong oxidant, it is convenient to consider the movement of a positively charged "hole" in a direction opposite to that of the electron.

Photoredox Catalysis Mediated by Tungsten(0) Arylisocyanides.

W(CNAr) (CNAr = arylisocyanide) photoreductants catalyze base-promoted homolytic aromatic substitution (BHAS) of 1-(2-iodobenzyl)-pyrrole in deuterated benzene. Moderate to high efficiencies correlate with W(CNAr) excited-state reduction potentials upon one-photon 445 nm excitation, with 10 mol % loading of the most powerful photoreductants W(CNDipp) (CNDipp = 2,6-diisopropylphenylisocyanide) and W(CNDippPh) (CNDippPh = 4-(3,4,5-trimethoxyphenyl)-2,6-diisopropylphenylisocyanide) affording nearly complete conversion. Stern-Volmer quenching experiments indicated that catalysis is triggered by substrate reductive dehalogenation.

Temperature Dependence of Charge and Spin Transfer in Azurin.

The steady-state charge and spin transfer yields were measured for three different Ru-modified azurin derivatives in protein films on silver electrodes. While the charge-transfer yields exhibit weak temperature dependences, consistent with operation of a near activation-less mechanism, the spin selectivity of the electron transfer improves as temperature increases. This enhancement of spin selectivity with temperature is explained by a vibrationally induced spin exchange interaction between the Cu(II) and its chiral ligands.

Dimeric Corrole Analogs of Chlorophyll Special Pairs.

Chlorophyll special pairs in photosynthetic reaction centers function as both exciton acceptors and primary electron donors. Although the macrocyclic natural pigments contain Mg(II), the central metal in most synthetic analogs is Zn(II). Here we report that insertion of either Al(III) or Ga(III) into an imidazole-substituted corrole affords an exceptionally robust photoactive dimer.

Design of robust 2,2'-bipyridine ligand linkers for the stable immobilization of molecular catalysts on silicon(111) surfaces.

The attachment of the 2,2'-bipyridine (bpy) moieties to the surface of planar silicon(111) (photo)electrodes was investigated using ab initio simulations performed on a new cluster model for methyl-terminated silicon. Density functional theory (B3LYP) with implicit solvation techniques indicated that adventitious chlorine atoms, when present in the organic linker backbone, led to instability at very negative potentials of the surface-modified electrode. In prior experimental work, chlorine atoms were present as a trace surface impurity due to required surface processing chemistry, and thus could plausibly result in the observed surface instability of the linker.

Photoinduced hole hopping through tryptophans in proteins.

Hole hopping through tryptophan/tyrosine chains enables rapid unidirectional charge transport over long distances. We have elucidated structural and dynamical factors controlling hopping speed and efficiency in two modified azurin constructs that include a rhenium(I) sensitizer, Re(His)(CO)(dmp), and one or two tryptophans (W, W). Experimental kinetics investigations showed that the two closely spaced (3 to 4 Å) intervening tryptophans dramatically accelerated long-range electron transfer (ET) from Cu to the photoexcited sensitizer.

Role of intramolecular hydrogen bonds in promoting electron flow through amino acid and oligopeptide conjugates.

Elucidating the factors that control charge transfer rates in relatively flexible conjugates is of importance for understanding energy flows in biology as well as assisting the design and construction of electronic devices. Here, we report ultrafast electron transfer (ET) and hole transfer (HT) between a corrole (Cor) donor linked to a perylene-diimide (PDI) acceptor by a tetrameric alanine (Ala) Selective photoexcitation of the donor and acceptor triggers subpicosecond and picosecond ET and HT. Replacement of the (Ala) linker with either a single alanine or phenylalanine does not substantially affect the ET and HT kinetics.

Synthesis, structural studies, and redox chemistry of bimetallic [Mn(CO)] and [Re(CO)] complexes.

Manganese ([Mn(CO)]) and rhenium tricarbonyl ([Re(CO)]) complexes represent a workhorse family of compounds with applications in a variety of fields. Here, the coordination, structural, and electrochemical properties of a family of mono- and bimetallic [Mn(CO)] and [Re(CO)] complexes are explored. In particular, a novel heterobimetallic complex featuring both [Mn(CO)] and [Re(CO)] units supported by 2,2'-bipyrimidine (bpm) has been synthesized, structurally characterized, and compared to the analogous monomeric and homobimetallic complexes.

Third-Generation W(CNAr) Photoreductants (CNAr = Fused-Ring and Alkynyl-Bridged Arylisocyanides).

Homoleptic tungsten(0) arylisocyanides possess photophysical and photochemical properties that rival those of archetypal ruthenium(II) and iridium(III) polypyridine complexes. Previous studies established that extending the π-system of 2,6-diisopropylphenylisocyanide (CNDipp) by coupling aryl substituents to the isocyanide functionality results in W(CNDippAr) oligoarylisocyanide complexes with greatly enhanced metal-to-ligand charge transfer (MLCT) excited-state properties relative to those of W(CNDipp). Extending electronic modifications to delineate additional design principles for this class of photosensitizers, herein we report a series of W(CNAr) compounds with naphthalene-based fused-ring (CN-1-(2-Pr)-Naph) and CNDipp-based alkynyl-bridged (CNDippAr) arylisocyanide ligands.