There are almost 500 naturally occurring variants of hemoglobin. Most are the result of a single amino acid substitution in a globin polypeptide chain. Some variants produce clinical illness, though not all variants have deleterious effects. A brief sample follows.

HbS (sickle-cell Hb): substitutes a Val for a Glu on the surface

Hb Cowtown: eliminates an ion pair involved in T-state stabilization

Hb Memphis: substitutes one uncharged polar residue for another of similar size on the surface Hb Bibba: substitutes a Pro for a Leu involved in an a helix

Hb Milwaukee: substitutes a Glu for a Val in the oxygen binding pocket

Hb Providence: substitutes an Asn for a Lys that normally projects into the central cavity of the tetramer Hb Philly: substitutes a Phe for a Tyr, disrupting hydrogen bonding at the a1b1 interface

Explain your choices for each of the following:

(a) The Hb variant least likely to cause pathological symptoms.

(b) The variant most likely to show a decrease in BPG binding and an increase in the overall affinity of the hemoglobin for oxygen.

(c) Increases the Kd of Hb for oxygen