title: The description of protein internal motions aids selection of ligand binding poses by the INPHARMA method.
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.
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stauch
authors.forename: Julien
authors.initials: J
authors.lastname: Orts
authors.forename: Teresa
authors.initials: T
authors.lastname: Carlomagno
mesh_terms: D017868:Cyclic AMP-Dependent Protein Kinases; D008024:Ligands; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D008024:Ligands; D011506:Proteins; D017868:Cyclic AMP-Dependent Protein Kinases