Trials and tribulations of the cubane paradigm in biomolecule discovery highlight synthetic limitations, culminating in a continuing guide for practitioners, which includes cyclooctatetraene.

The current report seeks to validate the existence of a post-transition state bifurcation in the Lewis acid-catalysed (4 + 3)-cycloaddition of butadiene and α-methoxy acrolein. Cycloaddition transition state (TS) structures are shown by intrinsic reaction coordinate (IRC) and potential energy surface (PES) scan calculations to connect directly to both (4 + 3)- and (4 + 2)-products. A second TS, a 1,2-sigmatropic shift which interconverts the products, was also located. Implicit solvent is observed to have a substantial effect of the course of the reaction, with the minimum energy path from the gas phase TS leading to (4 + 2)-product whereas the DCM solvent phase TS leads to (4 + 3)-product. On the basis of these data it is suggested that a number of previously reported (4 + 3)-cycloadditions may also possess reaction pathway bifurcations.

Glycosaminoglycans (GAGs) are a family of anionic carbohydrates that play an essential role in the physiology and pathology of all eukaryotic life forms. Experimental determination of GAG–protein complexes is challenging due to their difficult isolation from biological sources, natural heterogeneity, and conformational flexibilityincluding possible ring puckering of sulfated iduronic acid from 1C4 to 2SO conformation. To overcome these challenges, we present GlycoTorch Vina (GTV), a molecular docking tool based on the carbohydrate docking program VinaCarb (VC). Our program is unique in that it contains parameters to model 2SO sugars while also supporting glycosidic linkages specific to GAGs. We discuss how crystallographic models of carbohydrates can be biased by the choice of refinement software and structural dictionaries. To overcome these variations, we carefully curated 12 of the best available GAG and GAG-like crystal structures (ranging from tetra- to octasaccharides or longer) obtained from the PDB-REDO server and refined using the same protocol. Both GTV and VC produced pose predictions with a mean root-mean-square deviation (RMSD) of 3.1 Å from the native crystal structurea statistically significant improvement when compared to AutoDock Vina (4.5 Å) and the commercial software Glide (5.9 Å). Examples of how real-space correlation coefficients can be used to better assess the accuracy of docking pose predictions are given. Comparisons between statistical distributions of empirical “salt bridge” interactions, relevant to GAGs, were compared to density functional theory (DFT) studies of model salt bridges, and water-mediated salt bridges; however, there was generally a poor agreement between these data. Water bridges appear to play an important, yet poorly understood, role in the structures of GAG–protein complexes. To aid in the rapid prototyping of future pose scoring functions, we include a module that allows users to include their own torsional and nonbonded parameters.

By drawing analogies from the dimerization of cyclopentadiene, a novel reaction pathway bifurcation is uncovered in the cycloaddition of oxidopyrylium ylides and butadiene. Analysis of the potential energy surface (at the M06-2X/6-311+G(d,p) level of theory) in combination with Born−Oppenheimer molecular dynamics simulations (M06-2X/6-31+G(d)) demonstrate that both the (4 + 3)-and (5 + 2)-cycloaddition products are accessed from the same transition state. Key indicators of a pathway bifurcation (asynchronous bond formation, and a second transition state for the interconversion of the products) are also observed. The absence of a post-transition state bifurcation in the related oxidopyridinium systems of Krenske and Harmata is rationalized. Finally, the isosymmetry of the oxidopyrylium and cyclopentadiene molecular orbitals as well as the presence of "secondary orbital interactions" are emphasized as the common source of nonstatistical behavior. Application of these principles will allow for the rapid identification of new reaction pathway bifurcations.