Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

Tuning through-space interactions via the secondary coordination sphere of an artificial metalloenzyme leads to enhanced Rh(iii)-catalysis.

We report computationally-guided protein engineering of monomeric streptavidin Rh(iii) artificial metalloenzyme to enhance catalysis of the enantioselective coupling of acrylamide hydroxamate esters and styrenes. Increased TON correlates with calculated distances between the Rh(iii) metal and surrounding residues, underscoring an artificial metalloenzyme's propensity for additional control in metal-catalyzed transformations by through-space interactions.

Electrocatalytic Methane Functionalization with d0 Early Transition Metals Under Ambient Conditions.

The undesirable loss of methane (CH4 ) at remote locations welcomes approaches that ambiently functionalize CH4 on-site without intense infrastructure investment. Recently, we found that electrochemical oxidation of vanadium(V)-oxo with bisulfate ligand leads to CH4 activation at ambient conditions. The key question is whether such an observation is a one-off coincidence or a general strategy for electrocatalyst design. Here, a general scheme of electrocatalytic CH4 activation with d0 early transition metals is established. The pre-catalysts' molecular structure, electrocatalytic kinetics, and mechanism were detailed for titanium (IV), vanadium (V), and chromium (VI) species as model systems. After a turnover-limiting one-electron electrochemical oxidation, the yielded ligand-centered cation radicals activate CH4 with low activation energy and high selectivity. The reactivities are universal among early transition metals from Period 4 to 6, and the reactivities trend for different early transition metals correlate with their d orbital energies across periodic table. Our results offer new chemical insights towards developing advanced ambient electrocatalysts of natural gas.

Toxic and Physiological Metal Uptake and Release by Human Serum Transferrin.

An atomistic understanding of metal transport in the human body is critical to anticipate the side effects of metal-based therapeutics and holds promise for new drugs and drug delivery designs. Human serum transferrin (hTF) is a central part of the transport processes because of its ubiquitous ferrying of physiological Fe(III) and other transition metals to tightly controlled parts of the body. There is an atomistic mechanism for the uptake process with Fe(III), but not for the release process, or for other metals. This study provides initial insight into these processes for a range of transition metals-Ti(IV), Co(III), Fe(III), Ga(III), Cr(III), Fe(II), Zn(II)-through fully atomistic, extensive quantum mechanical/discrete molecular dynamics sampling and provides, to our knowledge, a new technique we developed to calculate relative binding affinities between metal cations and the protein. It identifies protonation of Tyr188 as a trigger for metal release rather than protonation of Lys206 or Lys296. The study identifies the difficulty of metal release from hTF as potentially related to cytotoxicity. Simulations identify a few critical interactions that stabilize the metal binding site in a flexible, nuanced manner.

Dehydrogenative B-H/C(sp3 )-H Benzylic Borylation within the Coordination Sphere of Platinum(II).

The first examples of stoichiometric dehydrogenative B-H/C(sp3 )-H benzylic borylation reactions, which are of relevance to catalytic methylarene (di)borylation, are reported. These unusual transformations involving a (κ2 -P,N)Pt(η3 -benzyl) complex, and either pinacolborane or catecholborane, proceed cleanly at room temperature. Density functional calculations suggest that borylation occurs via successive σ-bond metathesis steps, whereby a PtII -H intermediate engages in C(sp3 )-H bond activation-induced dehydrogenation.