Title: Development and Application of a Pantetheinyl Force Field for use in the Exploitation of the Biosynthesis of Fatty Acids, Polyketides, and Nonribosomal Peptides for “Unnatural” Natural Product Engineering
Abstract: Fatty acid synthases, polyketide synthases and nonribosomal peptide synthases can generate chemically diverse and complex bioactive natural products in an assembly line fashion. A common thread between these systems is the tethering of the growing intermediates and extender units to a carrier protein that has been post-translationally modified with a phosphopantetheine prosthetic group. The innate reactivity of phosphopantetheine-tethered intermediates has hampered our mechanistic understanding of protein-substrate and protein-protein interactions during the biosynthesis of these natural products, ultimately impeding the engineering of these systems for the generation of “unnatural” natural products. This research presentation outlines the development of a pantetheinyl-protein force field with comparison to experimental structural characterization, electronic structure calculations and normal-mode frequencies. This initial force field represents the first force field specifically designed to probe carrier protein-mediated natural product biosynthesis through in silico methods and provides a framework for an all-inclusive force field capable of handling natural or unnatural building blocks. Ultimately, this new tool will provide experimentalists with the ability to model these systems in silico and aid in the exploitation of these systems for the production of novel compounds.