We have studied the cation–π interactions of neutral aromatic ligands with the cationic amino acid residues arginine, histidine and lysine using ab initio calculations, symmetry adapted perturbation theory (SAPT), and a systematic meta-analysis of all available Protein Data Bank (PDB) X-ray structures. Quantum chemical potential energy surfaces (PES) for these interactions were obtained at the DLPNO-CCSD(T) level of theory and compared against the empirical distribution of 2012 unique protein–ligand cation–π interactions found in X-ray crystal structures. We created a workflow to extract these structures from the PDB, filtering by interaction type and residue pK_a. The gas phase cation–π interaction of lysine is the strongest by more than 10 kcal mol⁻¹, but the empirical distribution of 582 X-ray structures lies away from the minimum on the interaction PES. In contrast, 1381 structures involving arginine match the underlying calculated PES with good agreement. SAPT analysis revealed that underlying differences in the balance of electrostatic and dispersion contributions are responsible for this behavior in the context of the protein environment. The lysine–arene interaction, dominated by electrostatics, is greatly weakened by a surrounding dielectric medium and causes it to become essentially negligible in strength and without a well-defined equilibrium separation. The arginine–arene interaction involves a near equal mix of dispersion and electrostatic attraction, which is weakened to a much smaller degree by the surrounding medium. Our results account for the paucity of cation–π interactions involving lysine, even though this is a more common residue than arginine. Aromatic ligands are most likely to interact with cationic arginine residues as this interaction is stronger than for lysine in higher polarity surroundings.

This tutorial review outlines the theory and practice of computational modeling applied to understanding and predicting stereoselectivity.

Photoredox catalysis has transformed the landscape of radical-based synthetic chemistry. Additions of radicals generated through photo-redox catalysis to carbon–carbon pi bonds have become well-established; however, this approach has yet to be applied to the functionalization of carbon–carbon sigma bonds. Here we report the first such use of photoredox catalysis to promote the addition of organic hal-ides to the cage carbocycle [1.1.1]propellane; the product bicyclo[1.1.1]pentanes (BCPs) are motifs of high importance in the pharmaceutical industry, and in materials chemistry. Showing broad substrate scope and functional group tolerance, this methodology results in the first examples of bicyclopentylation of sp2 carbon–halogen bonds to access (hetero)arylated BCPs, as well as the functionalization of non-stabilized sp3 radicals. Substrates containing alkene acceptors allow the single-step construction of polycyclic bicyclopentane products through unprecedented atom transfer radical cyclization cascades, while the potential to accelerate drug discovery is demonstrated through late-stage bicyclopentylations of natural product- and drug-like molecules. Mechanistic investigations demonstrate the importance of the photocatalyst in this chemistry, and provide insight into the balance of radical stability and strain relief in the reaction cycle.

The cationic dummy atom approach provides a powerful nonbonded description for a range of alkaline-earth and transition-metal centers, capturing both structural and electrostatic effects. In this work we refine existing literature parameters for octahedrally coordinated Mn²⁺, Zn²⁺, Mg²⁺, and Ca²⁺, as well as providing new parameters for Ni²⁺, Co²⁺, and Fe²⁺. In all the cases, we are able to reproduce both M²⁺–O distances and experimental solvation free energies, which has not been achieved to date for transition metals using any other model. The parameters have also been tested using two different water models and show consistent performance. Therefore, our parameters are easily transferable to any force field that describes nonbonded interactions using Coulomb and Lennard-Jones potentials. Finally, we demonstrate the stability of our parameters in both the human and Escherichia coli variants of the enzyme glyoxalase I as showcase systems, as both enzymes are active with a range of transition metals. The parameters presented in this work provide a valuable resource for the molecular simulation community, as they extend the range of metal ions that can be studied using classical approaches, while also providing a starting point for subsequent parametrization of new metal centers.