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

Oakley AJ, Bhatia S, Ecroyd H, Garner B - PLoS ONE (2012)

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, New South Wales, Australia. aarono@uow.edu.au

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.

Methodology/principal findings: 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/significance: 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.

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Models of apoD interaction with 5-, 12- and 15-HpETE.ApoD with 5- (cyan carbon atoms) 12- (magenta carbon atoms) and 15-HpETE (yellow carbon atoms) modeled in the binding site. Met93 is shown. The expanded view illustrates the close proximity of the Met93 side chain to the HpETE peroxide moiety. The salt bridges between Arg62 and the fatty acid are also indicted in the expanded view as dashed lines.
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pone-0034057-g006: Models of apoD interaction with 5-, 12- and 15-HpETE.ApoD with 5- (cyan carbon atoms) 12- (magenta carbon atoms) and 15-HpETE (yellow carbon atoms) modeled in the binding site. Met93 is shown. The expanded view illustrates the close proximity of the Met93 side chain to the HpETE peroxide moiety. The salt bridges between Arg62 and the fatty acid are also indicted in the expanded view as dashed lines.

Mentions: The absence of appropriate parameters for lipid hydroperoxides in the CHARMM force-field currently precludes simulation of this class of molecule with apoD. Nevertheless, in order to understand how L-OOHs might bind to apoD, the peroxidized arachidonate products 5s-, 12s-, and 15s-HpETE were modeled based on the most stable low-energy conformation observed for arachidonate. The models are shown overlaid in Figure 6. These models suggest that the L-OOH molecules wrap around Met93 thus providing a plausible mechanism by which eicosatetraenoic acids bearing peroxides on different carbon atoms can interact with Met93 and give rise to Met93SO.


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

Oakley AJ, Bhatia S, Ecroyd H, Garner B - PLoS ONE (2012)

Models of apoD interaction with 5-, 12- and 15-HpETE.ApoD with 5- (cyan carbon atoms) 12- (magenta carbon atoms) and 15-HpETE (yellow carbon atoms) modeled in the binding site. Met93 is shown. The expanded view illustrates the close proximity of the Met93 side chain to the HpETE peroxide moiety. The salt bridges between Arg62 and the fatty acid are also indicted in the expanded view as dashed lines.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316614&req=5

pone-0034057-g006: Models of apoD interaction with 5-, 12- and 15-HpETE.ApoD with 5- (cyan carbon atoms) 12- (magenta carbon atoms) and 15-HpETE (yellow carbon atoms) modeled in the binding site. Met93 is shown. The expanded view illustrates the close proximity of the Met93 side chain to the HpETE peroxide moiety. The salt bridges between Arg62 and the fatty acid are also indicted in the expanded view as dashed lines.
Mentions: The absence of appropriate parameters for lipid hydroperoxides in the CHARMM force-field currently precludes simulation of this class of molecule with apoD. Nevertheless, in order to understand how L-OOHs might bind to apoD, the peroxidized arachidonate products 5s-, 12s-, and 15s-HpETE were modeled based on the most stable low-energy conformation observed for arachidonate. The models are shown overlaid in Figure 6. These models suggest that the L-OOH molecules wrap around Met93 thus providing a plausible mechanism by which eicosatetraenoic acids bearing peroxides on different carbon atoms can interact with Met93 and give rise to Met93SO.

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, New South Wales, Australia. aarono@uow.edu.au

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.

Methodology/principal findings: 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/significance: 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.

Show MeSH