Effector-Linked High-Frequency Thermal Fluctuations of Globin (Changes in Protein Dynamics) Regulate the Oxyge-Affinity and Cooperativity of Hemoglobin

Diatomic ligands such as O2, CO, and NO, which are dissociating from their binding sites (hemes) of myoglobin (Mb) and hemoglobin (Hb), are tentatively trapped at physical barriers of globin matrix (the “Caged” states) [1-5], before either [A] undergoing bimolecular dissociation to (deoxy state + free ligand) or [B] reverting back to re-bind to the hemes (geminate-recombination) [5]. Majorities of the un-bonded ligands take Route [B], while only small percentages of the un-bonded ligands proceed through Route [A] [5]. This causes substantial (>103 to 104-fold) increases in the apparent ligand-affinity for Mb and Hb, compared with that of free protoheme-N-base complexes [5]. It is well known that binding of heterotropic effectors reduces the O2-affinity of Hb (increases in P50), whereas binding of O2 does not change the P50 value of Hb. Effector-linked enhancements of high-frequency thermal fluctuations of globin [6] increase the transparency of globin matrix toward migrating diatomic ligands to enhance Route [A] and to diminish Route [B], resulted in substantial (up to >103-fold) decrease in the apparent O2-affinity (KT and KR) or (up to 100-fold increases in P50) without detectable changes in static crystallographic structures of Hb as well as the coordination/electronic structures of the hemes in T(deoxy)- and R(oxy)-Hb [5,7,8].References: [1] Yonetani, et al., Oxidases & Related Redox Systems, Vol. I, ed. T.E. King et al. (1973) pp. 401-405; [2] Iizuka, et al., BBA 351 (1974) 182-195; [3] Iizuka, et al., BBA 371 (1974) 126-139; [4] Yonetani, et al., JBC 249 (1974) 2168-2174; [5] Yonetani & Kanaori, BBA 1834 (2013) 1873-1884; [6] Laberge & Yonetani, Biophys. J. 94 (2008) 2737-2751; [7] Yonetani, et al., JBC 277 (2002) 34508-34520; [8] Yonetani & Laberge, BBA 1784 (2008) 1146-1158.