Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session VI Abstracts

Sickle Cell Hemoglobin: Allostery, Aggregation Kinetics, and Search for a Drug William Eaton . NIDDK, NIH, Bethesda, MD, USA Unlike other protein aggregation diseases, the molecular pathogenesis of sickle cell anemia is well understood. If sickle hemoglobin were at equilibrium in the tissues with respect to fiber formation, patients would not survive once fetal hemoglobin disappears after the first few weeks of life. The disease is survivable because of the highly unusual kinetics of fiber formation. Like amyloid formation, there is a delay period prior to fiber formation, which allows the vast majority of cells to escape the narrow vessels of the tissues before fibers make the red cells less deformable and cause vaso-occlusion. However, unlike amyloid formation, there is an enormous sensitivity of the kinetics to solution conditions, with the delay time inversely proportional to up to the 40 th power of the initial sickle hemoglobin concentration and a nucleation rate proportional to up to the 80 th power (no typos). The kinetics can be explained by a double nucleation mechanism, in which nucleation of new fibers on the surface of pre-existing fibers results in an autocatalytic time course that produces the delay period. In spite of our understanding of the thermodynamics and kinetics and their relation to pathogenesis, there is still only one partially successful drug, hydroxyurea, discovered more than 20 years ago, which replaces about 20% of sickle hemoglobin with fetal hemoglobin in up to 80% of cells. Hydroxyurea is therapeutic because it dilutes the sickle hemoglobin and increases the delay time. What is needed is a drug that acts on all cells. We have developed an automated laser-photolysis/image-analysis assay to screen for anti-sickling compounds. Our initial screen is being carried out on compounds already approved by the FDA for other human diseases. Compounds active in this screen would be rapidly approved for clinical trials.

35