The dynamic nature of carrier proteins, such as acyl carrier proteins (ACPs), makes their structures difficult to study via traditional techniques (i.e. x-ray crystallography and NMR). Site-specific vibrational spectroscopy is an extremely attractive way to study these proteins due to the short intrinsic time scale of the measurement, which can reveal details of conformational distribution at the site of probe installation. ACPs are of particular interest in bacterial biosynthetic pathways due to their integral role of ferrying intermediate substrates to desired active sites of enzymatic partners; understanding bacterial biosynthesis better can broaden our abilities to synthesize unnatural bioproducts using the cell’s machinery. One centrally important but poorly understood feature of ACPs is how they protect and present their growing substrates via “chain flipping” and/or “chain sequestration.” Growing substrates are tethered to the end of an ACP’s covalently attached phosphopantetheine (Ppant) arm. Depending on the (still not completely understood) interplay of ACP sequence, substrate chain length, and chain polarity, the arm can sequester itself in a hydrophobic cavity in some ACPs to protect the substrate and/or to cause a conformational change in the ACP that may allow it to recruit the next enzymic partner in the biosynthetic pathway.<br/>Vibrationally unique probe groups, such as thiocyanates and alkynes, have been placed with great success on the end of the Ppant arm. These probes have unique and strong vibrational peaks in otherwise unpopulated regions of the spectrum and are good reporters on the local solvent environment. Shifts in the vibrational probe peak’s frequency can be interpreted as evidence of the probe’s being solvent exposed or being sequestered in the nonpolar cavity. Recent work has focused on developing techniques to insert probes at different points throughout the arm and attached substrate to gain a more comprehensive understanding of the chemical environment around each component of the ACP-substrate complex, including the thioester substrate linkage that is the site of reactions leading to substrate elongation. Recent progress towards these new probe sites will be discussed.

Vibrational probes for arm and substrate dynamics in acyl carrier proteins

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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