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DOE OSTI · 2469706

Extended experimental inferential structure determination method in determining the structural ensembles of disordered protein states

Lincoff, James·Haghighatlari, Mojtaba·Krzeminski, Mickael·Teixeira, João C.·Gomes, Gregory-Neal W.·Gradinaru, Claudiu C.·Forman-Kay, Julie D.·Head-Gordon, Teresa
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Abstract

Proteins with intrinsic or unfolded state disorder comprise a new frontier in structural biology, requiring the characterization of diverse and dynamic structural ensembles. Here we introduce a comprehensive Bayesian framework, the Extended Experimental Inferential Structure Determination (X-EISD) method, which calculates the maximum log-likelihood of a disordered protein ensemble. X-EISD accounts for the uncertainties of a range of experimental data and back-calculation models from structures, including NMR chemical shifts, J-couplings, Nuclear Overhauser Effects (NOEs), paramagnetic relaxation enhancements (PREs), residual dipolar couplings (RDCs), hydrodynamic radii (R h ), single molecule fluorescence Förster resonance energy transfer (smFRET) and small angle X-ray scattering (SAXS). We apply X-EISD to the joint optimization against experimental data for the unfolded drkN SH3 domain and find that combining a local data type, such as chemical shifts or J-couplings, paired with long-ranged restraints such as NOEs, PREs or smFRET, yields structural ensembles in good agreement with all other data types if combined with representative IDP conformers.

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRYbiophysical chemistrymolecular modelling

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Lincoff, James, Haghighatlari, Mojtaba, Krzeminski, Mickael, Teixeira, João C., Gomes, Gregory-Neal W., Gradinaru, Claudiu C., Forman-Kay, Julie D., Head-Gordon, Teresa. 2020-06-09. Extended experimental inferential structure determination method in determining the structural ensembles of disordered protein states. https://doi.org/10.1038/s42004-020-0323-0

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