The making and breaking of σ bonds is an integral part of almost all photochemical reactions. Yet, the electronic states of σ electrons are not nearly as well understood as the states of π-electron systems. Efforts in our laboratory to enhance the current state of their understanding are described, using the specific example of oligosilanes. We address the intrinsically cyclic nature of σ delocalization and its dependence on chain length and conformation, both in terms of theory and spectroscopic experiments, from the simplest disilane chromophore to the spectral properties of the individual conformers of permethylated heptasilane. We also describe a new low-energy luminescence from certain conformers of permethylated oligosilanes.

Inhibition of protein–protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structural characterization of the surface using geometry-based pocket-detection methods. An attractive mapping strategy—that builds on the principles of fragment-based drug discovery (FBDD)—is to detect the fragment-centric modularity at the protein surface and then characterize the large PPI interface as a set of localized, fragment-targetable interaction regions. Here, we introduce AlphaSpace, a computational analysis tool designed for fragment-centric topographical mapping (FCTM) of PPI interfaces. Our approach uses the alpha sphere construct, a geometric feature of a protein’s Voronoi diagram, to map out concave interaction space at the protein surface. We introduce two new features—alpha-atom and alpha-space—and the concept of the alpha-atom/alpha-space pair to rank pockets for fragment-targetability and to facilitate the evaluation of pocket/fragment complementarity. The resulting high-resolution interfacial map of targetable pocket space can be used to guide the rational design and optimization of small molecule or biomimetic PPI inhibitors.

The use of peptidomimetic scaffolds to target protein–protein interfaces is a promising strategy for inhibitor design. The strategy relies on mimicry of protein motifs that exhibit a concentration of native hot spot residues. To address this constraint, we present a pocket-centric computational design strategy guided by AlphaSpace to identify high-quality pockets near the peptidomimetic motif that are both targetable and unoccupied. Alpha-clusters serve as a spatial representation of pocket space and are used to guide the selection of natural and non-natural amino acid mutations to design inhibitors that optimize pocket occupation across the interface. We tested the strategy against a challenging protein–protein interaction target, KIX/MLL, by optimizing a single helical motif within MLL to compete against the full-length wild-type MLL sequence. Molecular dynamics simulation and experimental fluorescence polarization assays are used to verify the efficacy of the optimized peptide sequence.

Resveratrol is a natural compound found in red wine that has been suggested to exert its potential health benefit through the activation of SIRT1, a crucial member of the mammalian NAD+-dependent deacetylases. SIRT1 has emerged as an attractive therapeutic target for many aging related diseases, however, how its activity can only be activated toward some specific substrates by resveratrol has been poorly understood. Herein, by employing extensive molecular dynamics simulations as well as fragment-centric topographical mapping of binding interfaces, we have clarified current controversies in the literature and elucidated that resveratrol plays an important activation role by stabilizing SIRT1/peptide interactions in a substrate-specific manner. This new mechanism highlights the importance of the N-terminal domain in substrate recognition, explains the activity restoration role of resveratrol toward some “loose-binding” substrates of SIRT1, and has significant implications for the rational design of new substrate-specific SIRT1 modulators.

The TD B3LYP/6-311G(d,p) method slightly overestimates the excitation energies of the first UV absorption band of the all-transoid conformers of SinMe2n + 2 (n = 2-8, 10), deduced from temperature-dependent measurements on conformer mixtures in hydrocarbon solvents, by a nearly constant amount (approximately 2000 cm-1). The TD B3LYP/6-31G(d) results are less satisfactory. The first band is calculated to be due to a sigma pi * excitation in Si2Me6 and to a superposition of overlapping sigma sigma * and sigma pi * excitations in the longer oligosilanes. The sigma pi * excitation is calculated to lie a little below the sigma sigma * excitation up to Si4Me10, the two transitions are nearly degenerate in Si5Me12, and the sigma sigma * excitation drops increasingly below the sigma pi * as the chain length is extended. The dipole strength of the sigma sigma * excitation grows by 4.8 D2 (D = debye) per added SiSi bond (more slowly up to n = 5) and the calculation overestimates it by a factor of about three. The sigma pi * excitation is computed to carry no or almost no oscillator strength, but as noted earlier by others, its presence is critical for the interpretation of the observed thermochromism. Upon cooling below room temperature, the first absorption maximum is blue-shifted in short chains and red-shifted in long chains. Unlike the prior investigators, we attribute the blue shift to the disappearance of hot bands built on the sigma pi * origin using intensity borrowing sigma-pi mixing vibrations (b1 in Si3Me8). As usual, the red shift is attributed to the disappearance of twisted conformers, which have higher calculated sigma sigma * excitation energies.