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.
Highlights
Hemoglobin (Hb) is a ubiquitous protein found in all kingdoms of life, i.e. in archaea, bacteria, fungi, protists, plants and animals [1]
This study aims to further elucidate the interaction of Hb-Hp complex at the molecular level through the use of molecular dynamics and protein-protein docking methods, focusing on how Hp can protect against toxic Hb radical formation
The protein structures were prepared for subsequent Molecular dynamics (MD) and docking simulations by removing heteroatoms as well as assigning appropriate protonation states for histidines and ionizable residues
Summary
Hemoglobin (Hb) is a ubiquitous protein found in all kingdoms of life, i.e. in archaea, bacteria, fungi, protists, plants and animals [1] It can inherently bind gaseous diatomic ligands such as O2, CO and NO via its heme prosthetic group, which is bound to the protein via the axial histidine ligands. The globin-fold of each monomeric chain is comprised of eight helices with A, E and F helices stacking on top of B, G and H helices Such structural topology is known as the 3-on-3 a-helical sandwich-fold while the 2-on-2 a-helical sandwich-fold, which is found in truncated Hb, places the B and E helices on top of the G and H helices. This globin-fold harbours the heme prosthetic group via coordination to the axially ligated histidine residues at the proximal and distal locations on the F and E helices, respectively
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