title: Molecular dynamics analysis of apolipoprotein-D-lipid hydroperoxide interactions: mechanism for selective oxidation of Met-93.
abstract: BACKGROUND
  Recent studies suggest reduction of radical-propagating fatty acid hydroperoxides to inert hydroxides by interaction with apolipoprotein-D (apoD) Met93 may represent an antioxidant function for apoD. The nature and structural consequences of this selective interaction are unknown.
  
  
  RESULTS
  Herein we used molecular dynamics (MD) analysis to address these issues. Long-timescale simulations of apoD suggest lipid molecules are bound flexibly, with the molecules free to explore multiple conformations in a binding site at the entrance to the classical lipocalin ligand-binding pocket. Models of 5s- 12s- and 15s-hydroperoxyeicosatetraenoic acids were created and the lipids found to wrap around Met93 thus providing a plausible mechanism by which eicosatetraenoic acids bearing hydroperoxides on different carbon atoms can interact with Met93 to yield Met93 sulfoxide (Met93SO). Simulations of glycosylated apoD indicated that a second solvent exposed Met at position 49 was shielded by a triantennerary N-glycan attached to Asn45 thereby precluding lipid interactions. MD simulations of apoD showed B-factors of the loop containing Met93SO were higher in the oxidized protein, indicating increased flexibility that is predicted to destabilize the protein and promote self-association.
  
  
  CONCLUSIONS
  These studies provide novel insights into the mechanisms that may contribute to the antioxidant function of apoD and the structural consequences that result if Met93SO is not redox-cycled back to its native state.
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, New South Wales, Australia. aarono@uow.edu.au
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Oakley
authors.forename: Surabhi
authors.initials: S
authors.lastname: Bhatia
authors.forename: Heath
authors.initials: H
authors.lastname: Ecroyd
authors.forename: Brett
authors.initials: B
authors.lastname: Garner
mesh_terms: D000595:Amino Acid Sequence; D000975:Antioxidants / Q000737:chemistry; D053399:Apolipoproteins D / Q000737:chemistry*; D001095:Arachidonic Acids / Q000737:chemistry; D001665:Binding Sites; D002942:Circular Dichroism; D003198:Computer Simulation; D005227:Fatty Acids / Q000737:chemistry; D005609:Free Radicals; D006801:Humans; D008054:Lipid Peroxides / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry; D008962:Models, Theoretical; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012997:Solvents / Q000737:chemistry; D013454:Sulfoxides / Q000737:chemistry*
chemical_list: C024328:APOD protein, human; D000975:Antioxidants; D053399:Apolipoproteins D; D001095:Arachidonic Acids; D005227:Fatty Acids; D005609:Free Radicals; D008054:Lipid Peroxides; D008055:Lipids; D012997:Solvents; D013454:Sulfoxides