The description of protein internal motions aids selection of ligand binding poses by the INPHARMA method

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Abstract

Protein internal motions influence observables of NMR experiments. The effect of internal motions occurring at the sub-nanosecond timescale can be described by NMR order parameters. Here, we report that the use of order parameters derived from Molecular Dynamics (MD) simulations of two holo-structures of Protein Kinase A increase the discrimination power of INPHARMA, an NMR based methodology that selects docked ligand orientations by maximizing the correlation of back-calculated to experimental data. By including internal motion in the back-calculation of the INPHARMA transfer, we obtain a more realistic description of the system, which better represents the experimental data. Furthermore, we propose a set of generic order parameters, derived from MD simulations of globular proteins, which can be used in the back-calculation of INPHARMA NOEs for any protein-ligand complex, thus by-passing the need of obtaining system-specific order parameters for new protein-ligand complexes. © Springer Science+Business Media B.V. 2012.

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Stauch, B., Orts, J., & Carlomagno, T. (2012). The description of protein internal motions aids selection of ligand binding poses by the INPHARMA method. Journal of Biomolecular NMR, 54(3), 245–256. https://doi.org/10.1007/s10858-012-9662-1

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