Redox active motifs in selenoproteins.

Selenoproteins use the rare amino acid selenocysteine (Sec) to act as the first line of defense against oxidants, which are linked to aging, cancer, and neurodegenerative diseases. Many selenoproteins are oxidoreductases in which the reactive Sec is connected to a neighboring Cys and able to form a ring. These Sec-containing redox motifs govern much of the reactivity of selenoproteins. To study their fundamental properties, we have used (77)Se NMR spectroscopy in concert with theoretical calculations to determine the conformational preferences and mobility of representative motifs. This use of (77)Se as a probe enables the direct recording of the properties of Sec as its environment is systematically changed. We find that all motifs have several ring conformations in their oxidized state. These ring structures are most likely stabilized by weak, nonbonding interactions between the selenium and the amide carbon. To examine how the presence of selenium and ring geometric strain governs the motifs' reactivity, we measured the redox potentials of Sec-containing motifs and their corresponding Cys-only variants. The comparisons reveal that for C-terminal motifs the redox potentials increased between 20-25 mV when the selenenylsulfide bond was changed to a disulfide bond. Changes of similar magnitude arose when we varied ring size or the motifs' flanking residues. This suggests that the presence of Sec is not tied to unusually low redox potentials. The unique roles of selenoproteins in human health and their chemical reactivities may therefore not necessarily be explained by lower redox potentials, as has often been claimed.

Orbital-based insights into parallel-displaced and twisted conformations in π-π interactions.

Dispersion and electrostatics are known to stabilize π-π interactions, but the preference for parallel-displaced (PD) and/or twisted (TW) over sandwiched (S) conformations is not well understood. Orbital interactions are generally believed to play little to no role in π-stacking. However, orbital analysis of the dimers of benzene, pyridine, cytosine and several polyaromatic hydrocarbons demonstrates that PD and/or TW structures convert one or more π-type dimer MOs with out-of-phase or antibonding inter-ring character at the S stack to in-phase or bonding in the PD/TW stack. This change in dimer MO character can be described in terms of a qualitative stack bond order (SBO) defined as the difference between the number of occupied in-phase/bonding and out-of-phase/antibonding inter-ring π-type MOs. The concept of an SBO is introduced here in analogy to the bond order in molecular orbital theory. Thus, whereas the SBO of the S structure is zero, parallel displacement or twisting the stack results in a non-zero SBO and overall bonding character. The shift in bonding/antibonding character found at optimal PD/TW structures maximizes the inter-ring density, as measured by intermolecular Wiberg bond indices (WBIs). Values of WBIs calculated as a function of the parallel-displacement are found to correlate with the dispersion and other contributions to the π-π interaction energy determined by the highly accurate density-fitting DFT symmetry adapted perturbation theory (DF-DFT-SAPT) method. These DF-DFT-SAPT calculations also suggest that the dispersion and other contributions are maximized at the PD conformation rather than the S when conducted on a potential energy curve where the inter-ring distance is optimized at fixed slip distances. From these results of this study, we conclude that descriptions of the qualitative manner in which orbitals interact within π-stacking interactions can supplement high-level calculations of the interaction energy and provide an intuitive tool for applications to crystal design, molecular recognition and other fields where non-covalent interactions are important.

Chalcogen bonding interactions between reducible sulfur and selenium compounds and models of zinc finger proteins.

Reducible sulfur and selenium (r-S/Se) compounds, defined as sulfur and selenium compounds not in the lowest -2 oxidation state (e.g., -1 to +6), release Zn(2+) from zinc-sulfur proteins such as zinc fingers (ZFs) and metallothionein. A series of density functional theory calculations was performed on donor-acceptor complexes between r-S/Se compounds and models of the Cys2His2, Cys3His and Cys4 ZF sites. These S⋯S/Se chalcogen bonding interactions consist of the donation of electron density from a S lone pair on the ZF model to a S/Se-X antibonding molecular orbital of the r-S/Se compound. The strength of the interaction was shown to be dependent upon the Lewis basicity of the ZF model (Cys4>Cys3His>Cys2His2) and the Lewis acidity of the r-S/Se compound as measured by the energy of the S/Se-X antibonding orbital. Interactions with the softer r-Se compounds were stronger than the r-S compounds, consistent with the greater reactivity of the former with ZF proteins.