Molecular dynamics analysis of apolipoprotein-D-lipid hydroperoxide interactions: mechanism for selective oxidation of Met-93

• Published in: PloS one 2012-03, Vol.7 (3), p.e34057-e34057
• Main Authors: Oakley, Aaron J, Bhatia, Surabhi, Ecroyd, Heath, Garner, Brett
• Format: Article
• Language: English
• Subjects: Acids; Alzheimer's disease; Alzheimers disease; Amino Acid Sequence; Amino acids; Analysis; Antioxidants; Antioxidants (Nutrients); Antioxidants - chemistry; Apolipoproteins; Apolipoproteins D - chemistry; Arachidonic Acids - chemistry; Binding Sites; Biology; Chemistry; Circular Dichroism; Computer Science; Computer Simulation; Dynamic tests; Fatty acids; Fatty Acids - chemistry; Free Radicals; Glycan; Humans; Hydroxides; Ligands; Lipid peroxidation; Lipid Peroxides - chemistry; Lipids; Lipids - chemistry; Lipocalin; Lipoproteins; Medical research; Membrane lipids; Models, Theoretical; Molecular dynamics; Molecular Dynamics Simulation; Molecular Sequence Data; Oxidation; Oxidation-Reduction; Protein Binding; Protein folding; Protein structure; Protein Structure, Tertiary; Self-association; Sequence Homology, Amino Acid; Solvents - chemistry; Sulfoxides - chemistry
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0034057

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. 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. 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.