On the Reference Structure for the Resonance Energy of Aromatic Hydrocarbons

To use the Zagreb Group and Aihara definition of resonance energy, it is necessary that the roots of the reference polynomial all be real. A partial proof that they are has been obtained in three ways. Direct solution of the reference polynomial for annulenes shows all roots real in this case. Application of Sturm sequences promises the complete proof in principle, but requires the proof of inequalities which we have so far resolved only for molecules with four or fewer atoms. A graph theoretical approach succeeds for all conjugated hydrocarbons in which no edge is shared by two rings. It is also suggested that the reference polynomial may be used for discriminating planar isospectral molecules

Bio-inspired Chemical Space Exploration of Terpenoids

Many computational methods are used to expand the open-ended border of chemical spaces. Natural products and their derivatives are an important source for drug discovery, and some algorithms are devoted to rapidly generating pseudo-natural products, while their accessibility and chemical interpretation were often ignored or underestimated, thus hampering experimental synthesis in practice. Herein, a bio-inspired strategy (named TeroGen) is proposed, in which the cyclization and decoration stage of terpenoid biosynthesis were mimicked by meta-dynamics simulations and deep learning models respectively, to explore their chemical space. In the protocol of TeroGen, the synthetic accessibility is validated by reaction energetics (reaction barrier and reaction heat) based on the GFN2-xTB methods. Chemical interpretation is an intrinsic feature as the reaction pathway is bioinspired and triggered by the RMSD-PP method in conjunction with an encoder-decoder architecture. This is quite distinct from conventional library/fragment-based or rule-based strategies, by using TeroGen, new reaction routes are feasibly explored to increase the structural diversity. For example, only a rather limited number of sesterterpenoids in our training set is included in this work, but our TeroGen would predict more than 30000 sesterterpenoids and map out the reaction network with super efficiency, ten times as many as the known sesterterpenoids (less than 2500). In sum, TeroGen not only greatly expands the chemical space of terpenoids but also provides various plausible biosynthetic pathways, which are crucial clues for heterologous biosynthesis, bio-mimic and chemical synthesis of complicated terpenoids

Biosynthesis of Spinosyn A: A [4 + 2] or [6 + 4] Cycloaddition?

SpnF, one of the Diels–Alderases, produces spinosyn A, and previous work demonstrated that its sole function is to catalyze the [4 + 2] cycloaddition (Fage, C. D.; et al. Nat. Chem. Biol. 2015, 11, 256−258). Furthermore, the potential existence of a [6 + 4] cycloaddition bifurcation from previous theoretical calculations on the nonenzyme model (Patel, A.; et al. J. Am. Chem. Soc. 2016, 138, 3631−3634) shows that the exact mechanism of SpnF becomes even more interesting as well as now being controversial. In the present work, QM­(DFT)/MM MD simulations on the full enzyme model revealed three significant residues that collaborate with other residues to control the direction of the cycloaddition, namely, Tyr23, Thr196, and Trp256. These residues force the substrate into a reactive conformation that causes the cycloaddition reaction to proceed through a [4 + 2] pathway instead of the [6 + 4] one. The mechanistic insights deciphered here are fundamentally important for the rational design of Diels–Alderases and biomimetic syntheses