Do Different Ligands Produce Different Effects in Sickle Hemoglobin Polymer Growth?

Abstract

Sickle Hemoglobin (HbS) is a variant of human hemoglobin with a point mutation on two subunits. This mutation causes HbS molecules to grow into polymers when the ligands it transports are released it and changes conformation from an R (relaxed) state to a T (tense) state. The polymer mass that grows inside a red blood cell can cause it to become too rigid to deform to pass through tight capillaries. This causes vaso occlusion and is one of many side effects of sickle cell disease. Polymer growth can be measured by fully photolyzing an HbS sample with a laser, thereby causing the solution molecules to release all their ligands and switch into a T-state. However, in vivo, the partial pressure of oxygen rarely falls below 50% which makes the Hb a combination of fully, partially and un-liganded species. Equilibrium and kinetic measurements were done previously on fractional O2, CO and NO species, although a complete systematic comparison has never been conducted to quantify all of the differing data. A comparison of previous data along with new kinetic results will be presented. Partially ligated crystal protein structures will also be employed to rationalize the results.