L Bertini

Silicon–Heteroaromatic [FeFe] Hydrogenase Model Complexes: Insight into Protonation, Electrochemical Properties, and Molecular Structures

To learn from Nature how to create an efficient hydrogen-producing catalyst, much attention has been paid to the investigation of structural and functional biomimics of the active site of [FeFe]-hydrogenase. To understand their catalytic activities, the μ-S atoms of the dithiolate bridge have been considered as possible basic sites during the catalytic processes. For this reason, a series of [FeFe]-H2 ase mimics have been synthesized and characterized. Different [FeFe]-hydrogenase model complexes containing bulky Si-heteroaromatic systems or fluorene directly attached to the dithiolate moiety as well as their mono-PPh3 -substituted derivatives have been prepared and investigated in detail by spectroscopic, electrochemical, X-ray diffraction, and computational methods. The assembly of the herein reported series of complexes shows that the μ-S atoms can be a favored basic site in the catalytic process. Small changes in the (hetero)-aromatic system of the dithiolate moiety are responsible for large differences in their structures. This was elucidated in detail by DFT calculations, which were consistent with the experimental results.

Inhibitors of the Cdc34 acidic loop: A computational investigation integrating molecular dynamics, virtual screening and docking approaches

Here, we carried out a computational study based on molecular dynamics, virtual screening and docking to identify potential inhibitory compounds of Cdc34, modulating the acidic loop conformation. The molecules identified in this study have been designed to act as molecular hinges that can bind the acidic loop in its closed conformation, thus inhibiting the Cdc34‐mediated ubiquitination cascade at the ubiquitin‐charging step. In particular, we proposed a pharmacophore model featuring two amino groups in the central part of the model and two lateral aromatic chains, which respectively establish electrostatic interactions with the acidic loop (Asp 108 and Glu 109) and a hydrogen bond with Ser 139, which is one of the key residues for Cdc34 activity.

Photocatalytic Hydrogen Evolution Driven by [FeFe] Hydrogenase Models Tethered to Fluorene and Silafluorene Sensitizers

It is successfully shown that photocatalytic proton reduction to dihydrogen in the presence of a sacrificial electron donor, such as trimethylamine (TEA) and ascorbate, can be driven by compact sensitizer-catalyst dyads, that is, dithiolate-bridged [FeFe] hydrogenase models tethered to organic sensitizers, such as fluorenes and silafluorenes (1u2009a-4u2009a). The sensitizer-catalyst dyads 1u2009a-4u2009a show remarkable and promising catalytic activities as well as enhanced stabilities during photocatalysis performed under UV-light irradiation. The photocatalysis was carried out both in non-aqueous and aqueous media. The latter experiments were performed by solubilizing the photocatalysts within micelles formed by either sodium dodecyl sulfate (SDS) or cetyltrimethylammonium bromide (CTAB). In this study a turnover number of 539 (7u2005h) is achieved under optimized conditions, which corresponds to an exceptionally high turnover frequency of 77u2005h-1 . Theoretical investigations as well as emission decay experiments were performed to understand the observed phenomena together with the mechanisms of photocatalytic H2 generation.

Interaction of the H-Cluster of FeFe Hydrogenase with Halides

FeFe hydrogenases catalyze H2 oxidation and production using an H-cluster, where two Fe ions are bound by an aza-dithiolate (adt) ligand. Various hypotheses have been proposed (by us and others) to explain that the enzyme reversibly inactivates under oxidizing, anaerobic conditions: intramolecular binding of the N atom of adt, formation of the so-called Hox/inact state or nonproductive binding of H2 to isomers of the H-cluster. Here, we show that none of the above explains the new finding that the anaerobic, oxidative, H2-dependent reversible inactivation is strictly dependent on the presence of Cl- or Br-. We provide experimental evidence that chloride uncompetitively inhibits the enzyme: it reversibly binds to catalytic intermediates of H2 oxidation (but not to the resting Hox state), after which oxidation locks the active site into a stable, saturated, inactive form, the structure of which is proposed here based on DFT calculations. The halides interact with the amine group of the H-cluster but do not directly bind to iron. It should be possible to stabilize the inhibited state in amounts compatible with spectroscopic investigations to explore further this unexpected reactivity of the H-cluster of hydrogenase.

Quantum Mechanical Methods for the Investigation of Metalloproteins and Related Bioinorganic Compounds

It is well known that transition metal ions are often bound to proteins, conveying very specific functional properties. In fact, metalloproteins play crucial biological roles in the transport and activation of small molecules such as H2, O2, and N2, as well as in several other biochemical processes. However, even if the presence of transition metals in the active site of proteins allows a very rich biochemistry, the experimental disclosure of structure-activity relationships in metalloproteins is generally difficult exactly because of the presence of transition metals, which are intrinsically characterized by a very versatile and often elusive chemistry. For this reason, computational methods are becoming very popular tools in the characterization of metalloproteins. In particular, since computing power is becoming less and less expensive, due to the continuous technological development of CPUs, the computational tools suited to investigate metalloproteins are becoming more accessible and therefore more commonly used also in molecular biology and biochemistry laboratories. Here, we present the main procedures and computational methods based on quantum mechanics, which are commonly used to study the structural, electronic, and reactivity properties of metalloproteins and related bioinspired compounds, with a specific focus on the practical and technical aspects that must be generally tackled to properly study such biomolecular systems.