title: A molecular dynamics simulation-based interpretation of nuclear magnetic resonance multidimensional heteronuclear spectra of α-synuclein·dopamine adducts.
abstract: Multidimensional heteronuclear nuclear magnetic resonance (NMR) spectroscopy provides valuable structural information about adducts between naturally unfolded proteins and their ligands. These are often highly pharmacologically relevant. Unfortunately, the determination of the contributions to observed chemical shifts changes upon ligand binding is complicated. Here we present a tool that uses molecular dynamics (MD) trajectories to help interpret two-dimensional (2D) NMR data. We apply this tool to the naturally unfolded protein human α-synuclein interacting with dopamine, an inhibitor of fibril formation, and with its oxidation products in water solutions. By coupling 2D NMR experiments with MD simulations of the adducts in explicit water, the tool confirms with experimental data that the ligands bind preferentially to (125)YEMPS(129) residues in the C-terminal region and to a few residues of the so-called NAC region consistently. It also suggests that the ligands might cause conformational rearrangements of distal residues located at the N-terminus. Hence, the performed analysis provides a rationale for the observed changes in chemical shifts in terms of direct contacts with the ligand and conformational changes in the protein.
authors: Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich ), D-52425 Jülich, Germany , and Institute for Advanced Simulation IAS-5, Computational Biomedicine, Forschungszentrum Jülich , D-52425 Jülich, Germany.
authors: Domenica
authors: D
authors: Dibenedetto
authors: Giulia
authors: G
authors: Rossetti
authors: Rocco
authors: R
authors: Caliandro
authors: Paolo
authors: P
authors: Carloni
mesh_terms: D004298:Dopamine / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D008024:Ligands; D051844:alpha-Synuclein; D004298:Dopamine