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. 2013 Apr 26;8(4):e62996.
doi: 10.1371/journal.pone.0062996. Print 2013.

Molecular modeling of the human hemoglobin-haptoglobin complex sheds light on the protective mechanisms of haptoglobin

Chanin Nantasenamat  1 , Virapong Prachayasittikul, Leif Bulow
Affiliations

Molecular modeling of the human hemoglobin-haptoglobin complex sheds light on the protective mechanisms of haptoglobin

Chanin Nantasenamat et al. PLoS One. .

Abstract

Hemoglobin (Hb) plays a critical role in human physiological function by transporting O2. Hb is safe and inert within the confinement of the red blood cell but becomes reactive and toxic upon hemolysis. Haptoglobin (Hp) is an acute-phase serum protein that scavenges Hb and the resulting Hb-Hp complex is subjected to CD163-mediated endocytosis by macrophages. The interaction between Hb and Hp is extraordinarily strong and largely irreversible. As the structural details of the human Hb-Hp complex are not yet available, this study reports for the first time on insights of the binding modalities and molecular details of the human Hb-Hp interaction by means of protein-protein docking. Furthermore, residues that are pertinent for complex formation were identified by computational alanine scanning mutagenesis. Results revealed that the surface of the binding interface of Hb-Hp is not flat and protrudes into each binding partner. It was also observed that the secondary structures at the Hb-Hp interface are oriented as coils and α-helices. When dissecting the interface in more detail, it is obvious that several tyrosine residues of Hb, particularly β145Tyr, α42Tyr and α140Tyr, are buried in the complex and protected from further oxidative reactions. Such finding opens up new avenues for the design of Hp mimics which may be used as alternative clinical Hb scavengers.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Structural fluctuation from MD simulation as described in terms of RMSD as a function of time for Hb (a), Hp (b), Hpα (c) and Hpβ (d).
Figure 2
Figure 2. Ensemble of structures from the last 10 ns of MD simulation for Hb (a), Hp (b) and Hpβ (c).
Figure 3
Figure 3. Top ranked structure of Hb-Hp from the best cluster of docking simulation is shown from the side (a) and top (b) view.
Figure 4
Figure 4. Top ranked structure of Hb-Hpβ from the best cluster of docking simulation is shown from the side (a) and top (b) view.
Figure 5
Figure 5. Residues at the binding interfaces of Hb and Hp from docking complexes of Hb-Hp are displayed as yellow colored sticks.
Figure 6
Figure 6. Residues at the binding interfaces of Hb and Hpβ from docking complexes of Hb-Hpβ are displayed as yellow colored sticks.
Figure 7
Figure 7. Molecular modeling analysis at the binding interface of the top ranked complex of Hb-Hp with particular focus on βTrp37 of Hb (a) and βPhe131 of Hp (b).
The former panel shows βTrp37 of Hb participating in π-π ring stacking interaction with two neighboring phenylalanines of Hp, βPhe129 and βPhe131, as well as engaging in π-cation interaction with a nearby lysine of Hp, βLys130. The latter panel shows βPhe131 of Hp taking part in intermolecular π-π stacking interactions with aromatic residues of Hb, βTyr35 and βTrp37. In addition to the inner sphere of aromatic residues of Hb (comprising of βTyr35 and βTrp37), a second outer sphere of aromatic residues of Hb (comprising of βPhe41 and βPhe42) is also present.
Figure 8
Figure 8. Molecular models of Hb-Hp complex as obtained from protein-protein docking calculations revealed that the penultimate tyrosine residues, βTyr145 (a) and αTyr140 (b), are situated right at the binding interface and are located on opposite side of the protein.
αTyr42 of Hb (b) as well as the heme prosthetic group of both α and β-chains are located at a distance from the binding interface.
Figure 9
Figure 9. Structure superimposition of modeled (cyan) and crystal (green) structure of Hb-Hp complex (a) as well as Hp (b) and Hb (c) structures.
See this image and copyright information in PMC

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