Determination of Ligand Pathways in Globins

Abstract

Background: O 2 pathways in animal hemoglobins and myoglobins are controversial. Results: Ligands enter and exit sperm whale Mb and Cerebratulus lacteus Hb by completely different pathways. Conclusion: Rational mutagenesis mapping can identify ligand migration pathways and provides experimental benchmarks for testing molecular dynamics simulations. Significance: Globins can use either a polar gate or an apolar tunnel for ligand entry.

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

“…Such alternative migration pathways have been observed in other globins, such as in the Mycobacterium tuberculosis truncated Hb N (58 -60) and in the Cerebratulus lacteus neuronal mini-globin (18), in which very clear apolar tunnels appear to be the main routes for ligand migration and not the E7 channel. In mammalian Mbs and Hbs, however, extensive experimental evidence has pointed to the E7 channel as the principal avenue for ligand migration (8,11,12,18). Our calculated free energy profiles for both the open and closed His-E7 conformational states also lend considerable support to the E7 channel being a principal ligand migration route in Mb.…”

NO2−-mediated nitrosylation of ferrous microperoxidase-11

“…Cavity/tunnel systems represent a preferential guide(s) for ligand access to the catalytic center, limit the freedom degrees of the ligand conformation, and decrease the energy barrier(s) for ligand binding to the heme-Fe atom [57,58]. Of note, ferrous Synechocystis truncated hemoglobin as well as C. reinhardtii truncated hemoglobin 1-1 and 1-2, which are characterized by cavity/tunnel systems [38,59], display fast rate constants for NO 2 − conversion to NO (see Table 1) [35,38] in spite of a fairly hidden hexacoordinated heme-Fe(II) [38,59].…”

Myoglobin oxygen affinity in aquatic and terrestrial birds and mammals

“…Because of this, ligand entry must rely on amino acid side chain fluctuations to open transient channels leading from the protein surface to the distal pocket. There are several proposed transient ligand channels involving the Xe pockets, but the majority (>75%) of ligand movement in and out of Mb appears to be through a rotation of the distal histidine which serves as a gate to open a direct channel from the protein surface to the distal pocket where heme binding can occur (Scott et al, 2001;Salter et al, 2012). Variation in globin structure that affects the kinetics of binding or releasing oxygen will alter its oxygen affinity (Harada et al, 2007; and mutations that selectively stabilize the oxygen-bound form will increase oxygen affinity (Ajloo et al, 2002).…”