title: Computational studies of the cholesterol transport between NPC2 and the N-terminal domain of NPC1 (NPC1(NTD)).
abstract: The transport of cholesterol from NPC2 to NPC1 is essential for the maintenance of cholesterol homeostasis in late endosomes. On the basis of a rigid docking model of the crystal structures of the N-terminal cholesterol binding domain of NPC1(NTD) and the soluble NPC2 protein, models of the NPC1(NTD)-NPC2-cholesterol complexes at the beginning and the end of the transport as well as the unligated NPC1(NTD)-NPC2 complex were studied using 86 ns MD simulations. Significant differences in the cholesterol binding mode and the overall structure of the two proteins compared to the crystal structures of the cholesterol binding separate units were obtained. Relevant residues for the binding are identified using MM/GBSA calculations and the influence of the mutations analyzed by modeling them in silico, rationalizing the results of previous mutagenesis experiments. From the calculated energies and the NEB (nudged elastic band) evaluation of the cholesterol transfer mechanism, an atomistic model is proposed of the transfer of cholesterol from NPC2 to NPC1(NTD) through the formation of an intermediate NPC1(NTD)-NPC2 complex.
authors.affiliation: Department of Chemistry and Biochemistry and the Center for Rare and Neglected Diseases, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Estiu
authors.forename: Nazir
authors.initials: N
authors.lastname: Khatri
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiest
mesh_terms: D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D019295:Computational Biology; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins; D002784:Cholesterol