Hemoglobin is the oxygen transport protein of our cardiovascular system. Functional hemoglobin is a tetramer with each monomeric subunit encapsulating a metallocofactor heme that binds oxygen. Genetic mutations can cause hemoglobin misassembly or impaired hemoglobin stability diseases by altering inter-subunit interfaces or by disrupting heme binding in the subunits. The tetrameric interfaces in hemoglobin regulate cooperative binding of oxygen to heme iron. We are implementing atomic level molecular dynamics (MD) simulations, combined with thermodynamics integration calculations, in order to evaluate the free energy changes associated with this cooperativity across mutations affecting inter-subunit interactions at the tetramer interfaces. Recent advancements in AMBER’s free energy algorithms for accelerated execution on graphical processing units have enabled us to pursue in silico thermodynamics studies of large biomolecules such as hemoglobin at unprecedented time scales. We are also performing MD simulations to examine hemin (ferric heme) disassociation pathways in human hemoglobins. We have already determined experimentally, using spectroscopy and small angle X-ray scattering methods, that heme disassociation causes the tetrameric hemoglobin to completely disassemble and unfold. Our MD simulations now reveal that hemichromes, which have been observed to accumulate in certain hemoglobin misassembly diseases, are on-pathway intermediates in folded hemoglobins before hemin starts to disassociate. Hemichromes occur when both axial sites of hemin iron coordinate with amino acids. During the simulations, we observed hemin disassociation to be promoted by clinically relevant mutations that either introduce heme cavity packing deficiencies or disrupt hemichrome formation. Through our simulations, we were also able to determine that the initial stages of hemoglobin disassembly are prefaced by both alpha-helical structure loss surrounding the heme cavity and disruption of specific tetramer interface interactions. Overall, using MD simulations, we have structurally characterized and evaluated critical atomic interactions and disassembly intermediates that are difficult to isolate and identify for hemoglobin by conventional spectroscopy and X-ray crystallography methods. Eventually, this research will guide targeted therapy design for unstable hemoglobin genotypes.

Molecular dynamics simulations unravel the mysteries of unstable hemoglobin diseases

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.