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Sequence Controlled Secondary Structure Is Important for the Site-selectivity of Lanthipeptide Cyclization Taken together, these findings will facilitate our understanding of the lanthipeptide biosynthetic mechanism and accelerate bioengineering efforts for lanthipeptide-derived products. Our findings indicate that the substrate sequence and its solution structure can be used to predict the site-selectivity and order of ring formation, and that secondary structure is a crucial factor influencing the site-selectivity. Simulation results indicate that in both cases, C-terminal ring formation is more likely which was supported by experimental results. In addition, we performed simulation for ProcA1.1 and 2.8, which are well-suited candidates to investigate the connection between order of ring formation and solution structure. We also demonstrate that the dehydration step in the biosynthesis pathway does not influence the site-selectivity of ring formation. Our simulation results support a model in which the secondary structure of the core peptide is important for the final product’s ring pattern for the substrates investigated. In this study, we performed molecular dynamic simulations for ProcA3.3 variants to explore how the predicted solution structure of the substrate without enzyme correlates to the final product formation. However, exactly how substrate sequence contributes to site-selective lanthipeptide biosynthesis is not clear. Previous studies suggested that the site-selectivity of lanthionine formation is determined by substrate sequence rather than by the enzyme. It is enigmatic that a single enzyme can catalyze the cyclization process of many substrates with high fidelity. ProcM, a class II lanthipeptide synthetase, demonstrates high substrate tolerance. Lanthipeptides are ribosomally synthesized and post-translationally modified peptides that are generated from precursor peptides through a dehydration and cyclization process.
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