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# What causes red blood cells to sickle?

## Problem

Sickle cell disease is an autosomal recessive disease commonly found in African populations. The disease gets its name from the fact that patients’ red blood cells become sickle-shaped when passing through the capillaries of metabolically active tissues. These red blood cells become frail and can rupture long before their normal lifespan. The sickled red blood cells block capillaries and inhibit red blood cell function, causing severe anemia in sufferers.
The most common hemoglobin of adults is hemoglobin A (H, b, start superscript, start text, A, end text, end superscript). However patients suffering from sickle cell disease are homozygous for the allele coding for the abnormal variant of hemoglobin (H, b, start superscript, start text, S, end text, end superscript) due to a missense mutation in the gene encoding the β subunit of hemoglobin. This missense mutation replaces glutamic acid with valine at the sixth position of the β-globin chain.
The absence of a polar amino acid at this position promotes the non-covalent aggregation of hemoglobin in a low-oxygen environment which distorts red blood cells into a sickle shape and decreases their elasticity. Biochemically, the low oxygen environment causes the beta chain of neighboring hemoglobin molecules to hook together, becoming rigid and polymerized. These cells fail to return to their normal shape when oxygen is restored and thus fail to deform as they pass through narrow vessels, leading to blockage in the capillaries.
In vitro studies of deoxygenation and reoxygenation of sickle-cell hemoglobin indicates that the process is reversible. The hemoglobin molecules polymerize and form crystals as oxygen concentration is lowered. But as the oxygen concentration is increased again, hemoglobin molecules can depolymerize and return to their soluble state. This can be written as:
Figure 1. The equilibrium reaction equation relates non-sickled hemoglobin with sickle cell hemoglobin polymers.
The discovery of the sickle cell mutation came from isoelectric focusing, a type of electrophoresis that separates complex mixtures of large molecules by applying an electric current. Hemoglobin taken from patients suffering from sickle cell anemia, individuals who were heterozygous for the abnormal variant, and those that did not have the sickle cell allele were subjected to isoelectric focusing, the following results were obtained:
Figure 2. Distribution of hemoglobin protein position along gel after isoelectric focusing.
Data adapted from: Natural Sciences Learning Center, Washington University. (2003). The Molecular Biology of Sickle Cell Anemia.
Which of the following amino acids, if present at the sixth position of the β-globin chain, would yield a non-covalent aggregation of hemoglobin in a low-oxygen environment?