The biosynthesis of polyketide natural products is centrally dependent on a class of proteins called acyl carrier proteins (ACPs). ACPs covalently bind intermediates to a 4’-Phosphopantetheine (Ppant) arm that is covalently bound to a conserved serine residue. The movement of this arm allows ACPs to both protect growing intermediates through selective sequestration inside the ACP and shuttle intermediates to various catalytic domains for further chemical modification.<br/>Site specific vibrational spectroscopy experiments of nitrile probe groups have revealed the local environment of the end of the Ppant arm, showing general promise for reporting dynamic structural changes that occur on anything slower than the picosecond time scale. Truly quantitative interpretation of these data is challenging, however. Studies with these nitrile probes can potentially provide an estimate for the binding constant between <i>ACPs</i> and partner enzymes, along with resulting dynamic structural changes. Molecular dynamics simulations are performed to further our understanding of the spectroscopic data from the nitrile probe groups by providing a structural explanation for observed lineshapes. Comparison of the structural ensembles from MD simulations with and without the artificial probe groups also provides a new way to determine whether the probe has perturbed the native structure and/or dynamics of the ACP.<br/>MD simulations of various ACPs are being performed using Gromacs with the Charmm36m force field, with a pre-validated modification for the thiocyanate nitrile probe group; simulated observables such as solvent-accessible surface area of the probe group can provide an approximate interpretation of experimental data. Spectroscopic lineshapes will be simulated using vibrational frequencies from effective fragment potential-based vibrational frequency shift calculations.

Computational simulation of structural dynamics and vibrational spectra for probe groups in acyl carrier proteins

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

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.