title: Characterization of the molten globule state of retinol-binding protein using a molecular dynamics simulation approach.
abstract: Retinol-binding protein transports retinol, and circulates in the plasma as a macromolecular complex with the protein transthyretin. Under acidic conditions retinol-binding protein undergoes a transition to the molten globule state, and releases the bound retinol ligand. A biased molecular dynamics simulation method has been used to generate models for the ensemble of conformers populated within this molten globule state. Simulation conformers, with a radius of gyration at least 1.1 A greater than that of the native state, contain on average 37%beta-sheet secondary structure. In these conformers the central regions of the two orthogonal beta-sheets that make up the beta-barrel in the native protein are highly persistent. However, there are sizable fluctuations for residues in the outer regions of the beta-sheets, and large variations in side chain packing even in the protein core. Significant conformational changes are seen in the simulation conformers for residues 85-104 (beta-strands E and F and the E-F loop). These changes give an opening of the retinol-binding site. Comparisons with experimental data suggest that the unfolding in this region may provide a mechanism by which the complex of retinol-binding protein and transthyretin dissociates, and retinol is released at the cell surface.
authors.affiliation: Institute of Molecular Biophysics, School of Physics and Astronomy, University of Leeds, UK. e.paci@leeds.uk
authors.forename: Emanuele
authors.initials: E
authors.lastname: Paci
authors.forename: Lesley H
authors.initials: LH
authors.lastname: Greene
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Jones
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Smith
mesh_terms: D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D009038:Motion; D044367:Phase Transition; D011228:Prealbumin / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012177:Retinol-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma
chemical_list: D011228:Prealbumin; C101326:RBP4 protein, human; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma