Radicalized DNA Bases through Ring-Expansion Modification: An Intriguing Class of Building Blocks for the Magnetic DNA Nanowires

In the present work, cyclopentadienyl radicals are introduced to nucleobases to gain the building blocks of DNA-based molecular wires with novel electromagnetic characteristics. Calculations reveal that the radicalized DNA bases exist stably because their extended π-conjugated structures are beneficial to spin delocalization, diradical base pairs possess open-shell singlet ground states, and magnetic coupling interactions of the multiradical systems are controlled by both intra- and intermolecular interactions. For the designed base pairs, the intra-base-pair magnetic interactions are weak, especially in the diradical rA–rT base pair; as for the inter-base-pair magnetic interactions, different cases are observed depending on the relative position of the radicalized bases. The overlap-stacking diradical helices manifest variable degrees of ferromagnetic and antiferromagnetic characteristics, whereas the magnetic coupling interactions in the cross-stacking diradical helices are generally weak. The latter is attributed to the long spatial distances between the two spin centers. Thus, for the tetraradical helices, their magnetic characteristics can be viewed as a combination of two overlap-stacking diradical base pairs, and mostly are antiferromagnetic. This work provides a reasonable strategy of designing magnetic building blocks for the magnetic DNA molecular wires or DNA molecular magnets

3₁₀-Helical Peptide Acting as a Dual Relay for Charge-Hopping Transfer in Proteins

We present a density functional calculational study to clarify that a 3₁₀-helix peptide can serve as a novel dual-relay element to mediate long-range charge migrations via its C- and N-termini in proteins. The ionization potential of the 3₁₀-helix C-terminus correlates inversely with the helix length, HOMO energy, and dipole moment. In particular, it decreases considerably with the increase in the number of peptide units, even to a smaller value than that of the easily oxidized amino acid residue, which implies the possibility of releasing an electron and forming a hole at the 3₁₀-helical C-terminus. On the other hand, the electron affinity of the 3₁₀-helical N-terminus correlates positively with the helix length and dipole moment but inversely with the LUMO energy. Clearly, the increasing positive electron-binding energy with the increase in the number of peptide units implies that the 3₁₀-helical N-terminus can capture an excess electron and play an electron-relaying role. The relaying ability of the 3₁₀-helical C-terminus and N-terminus not only depends on the helix length but also varies subject to the capping effect, the collaboration and competition of proximal groups, and solvent environments. In contrast to the known hole relays such as the side chains of Tyr and Trp and electron relays such as the side chains of protonated Lys and Arg, either the hole relay (the 3₁₀-helix C-terminus) or the electron relay (the 3₁₀-helix N-terminus) is property-tunable and could apply to different proteins in assisting or mediating long-range charge migrations

Multi-Zinc-Expanded Oligoacenes: An Intriguing Class of Well-Defined Open-Shell Singlet Diradicals

Two classes of multi-Zn-expanded oligoacenes from benzene to pentacene are computationally designed through introducing a Zn array into acene rings in two ways: acene-chain axial versus single-ring quasi-transversal direction. Combined density functional theory, CASSCF, and CCSD calculations predict that all these multi-Zn-expanded oligoacenes have the open-shell singlet diradical ground states, in contrast with the common fact that their parent oligoacenes are closed-shell systems or may have a triplet ground state and only acenes larger than octacene have open-shell singlet diradical ground states. These results offer the first theoretical prediction that the multi-Zn introduction into the acene ring­(s), forming the Zn-expanded oligoacenes, can lead them to diradical structures. The diradical character of the ground states of these molecules arises from the Zn-participation-induced disjoint nature of the nonbonding molecular orbitals that are singly occupied in the diradicals. This work provides a strategy to design perfect and stable singlet diradicals from oligoacenes or their derivatives

Radical–Radical Interactions among Oxidized Guanine Bases Including Guanine Radical Cation and Dehydrogenated Guanine Radicals

We present here a theoretical investigation of the structural and electronic properties of di-ionized GG base pairs (G^•+G^•+,G­(-H1)^•G^•+, and G­(-H1)^•G­(-H1)^•) consisting of the guanine cation radical (G^•+) and/or dehydrogenated guanine radical (G­(-H1)^•) using density functional theory calculations. Different coupling modes (Watson–Crick/WC, Hoogsteen/Hoog, and minor groove/min hydrogen bonding, and π–π stacking modes) are considered. We infer that a series of G^•+G^•+ complexes can be formed by the high-energy radiation. On the basis of density functional theory and complete active space self-consistent (CASSCF) calculations, we reveal that in the H-bonded and N–N cross-linked modes, (G^•+G^•+)_WC, (G­(-H1)^•G­(-H1)^•)_WC, (G­(-H1)^•G­(-H1)^•)_minI, and (G­(-H1)^•G­(-H1)^•)_minIII have the triplet ground states; (G^•+G^•+)_HoogI, (G­(-H1)^•G^•+)_WC, (G­(-H1)^•G^•+)_HoogI, (G­(-H1)^•G^•+)_minI, (G­(-H1)^•G^•+)_minII, and (G­(-H1)^•G­(-H1)^•)_minII possess open-shell broken-symmetry diradical-characterized singlet ground states; and (G^•+G^•+)_HoogII, (G^•+G^•+)_minI, (G^•+G^•+)_minII, (G^•+G^•+)_minIII, (G^•+G^•+)_HoHo, (G­(-H1)^•G^•+)_minIII, (G­(-H1)^•G^•+)_HoHo, and (G­(-H1)^•G­(-H1)^•)_HoHo are the closed-shell systems. For these H-bonded diradical complexes, the magnetic interactions are weak, especially in the diradical G^•+G^•+ series and G­(-H1)^•G­(-H1)^• series. The magnetic coupling interactions of the diradical systems are controlled by intermolecular interactions (H-bond, electrostatic repulsion, and radical coupling). The radical–radical interaction in the π–π stacked di-ionized GG base pairs ((G^•+G^•+)_ππ, (G­(-H1)^•G^•+)_ππ, and (G­(-H1)^•G­(-H1)^•)_ππ) are also considered, and the magnetic coupling interactions in these π–π stacked base pairs are large. This is the first theoretical prediction that some di-ionized GG base pairs possess diradical characters with variable degrees of ferromagnetic and antiferromagnetic characteristics, depending on the dehydrogenation characters of the bases and their interaction modes. Hopefully, this work provides some helpful information for the understanding of different structures and properties of the di-ionized GG base pairs

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein

Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of <i>Mycobacterium tuberculosis</i> InhA

Tuberculosis (TB) is one of the world’s oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from <i>Mycobacterium tuberculosis</i>, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound <b>7</b> endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure–activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound <b>65</b>