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Title
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Determination of ligand pathways in globins apolar tunnels versus polar gates
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Author
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Abstract
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| Although molecular dynamics simulations suggest multiple interior pathways for O-2 entry into and exit from globins, most experiments indicate well defined single pathways. In 2001, we highlighted the effects of large-to-small amino acid replacements on rates for ligand entry and exit onto the three-dimensional structure of sperm whale myoglobin. The resultant map argued strongly for ligand movement through a short channel from the heme iron to solvent that is gated by the distal histidine (His-64(E7)) near the solvent edge of the porphyrin ring. In this work, we have applied the same mutagenesis mapping strategy to the neuronal mini-hemoglobin from Cerebratulus lacteus (CerHb), which has a large internal tunnel from the heme iron to the C-terminal ends of the E and H helices, a direction that is 180 opposite to the E7 channel. Detailed comparisons of the new CerHb map with expanded results for Mb show unambiguously that the dominant (> 90%) ligand pathway in CerHb is through the internal tunnel, and the major (> 75%) ligand pathway in Mb is through the E7 gate. These results demonstrate that: 1) mutagenesis mapping can identify internal pathways when they exist; 2) molecular dynamics simulations need to be refined to address discrepancies with experimental observations; and 3) alternative pathways have evolved in globins to meet specific physiological demands. |
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Language
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English
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Source (journal)
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Journal of biological chemistry. - Baltimore, Md
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Publication
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Baltimore, Md
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2012
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ISSN
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0021-9258
[print]
1083-351X
[online]
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DOI
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10.1074/JBC.M112.392258
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Volume/pages
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287
:40
(2012)
, p. 33163-33178
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ISI
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000309602100008
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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