Comment on "Substrate Folding Modes in Trichodiene Synthase: A Determinant of Chemo- and Stereoselectivity".

Wang et al. recently reported an in silico study of the trichodiene synthase (TDS) conversion of farnesyl diphosphate (FPP) to trichodiene (TD) (Wang et al., ACS Catal. 2017, 7 , 5841-5846). Although the methods and level of theory used in that work are nearly identical to our own recent work on this system (Dixit et al., ACS Catal. 2017, 7 , 812-818), Wang et al. reach rather different conclusions. The authors claimed to obtain a "very credible" mechanism for the biosynthesis of TD and optimized the optimal folding mode of FPP in the 1,6-ring closure in TDS. However, the folding mode of the FPP substrate that was presented contradicts well-established NMR and mass spectrometry data. Moreover, the authors make numerous incorrect statements regarding our earlier work.