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Effects of mutations on the molecular dynamics of oxygen escape from the dimeric hemoglobin of Scapharca inaequivalvis.

Trujillo K, Papagiannopoulos T, Olsen KW - F1000Res (2015)

Bottom Line: Locally enhanced sampling molecular dynamics are used here to suggest alternative pathways in the wild-type and six mutant proteins.In most cases the point mutations change the selection of exit routes observed in the simulations.Exit via the histidine gate is rarely seem although oxygen molecules do occasionally cross over the interface from one subunit to the other.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, IL, 60660, USA.

ABSTRACT
Like many hemoglobins, the structure of the dimeric hemoglobin from the clam Scapharca inaequivalvis is a "closed bottle" since there is no direct tunnel from the oxygen binding site on the heme to the solvent.  The proximal histidine faces the dimer interface, which consists of the E and F helicies.  This is significantly different from tetrameric vertebrate hemoglobins and brings the heme groups near the subunit interface. The subunit interface is also characterized by an immobile, hydrogen-bonded network of water molecules.  Although there is data which is consistent with the histidine gate pathway for ligand escape, these aspects of the structure would seem to make that pathway less likely. Locally enhanced sampling molecular dynamics are used here to suggest alternative pathways in the wild-type and six mutant proteins. In most cases the point mutations change the selection of exit routes observed in the simulations. Exit via the histidine gate is rarely seem although oxygen molecules do occasionally cross over the interface from one subunit to the other. The results suggest that changes in flexibility and, in some cases, creation of new cavities can explain the effects of the mutations on ligand exit paths.

No MeSH data available.


Related in: MedlinePlus

A. M37V trajectories showing the internal cavities used for oxygen escape.B. M37F trajectories reveal the internal cavities for ligand transport. The relative position of each internal cavity can be compared to the B, Xe4, Xe2, and Xe1 cavities inFigure 2B.
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f5: A. M37V trajectories showing the internal cavities used for oxygen escape.B. M37F trajectories reveal the internal cavities for ligand transport. The relative position of each internal cavity can be compared to the B, Xe4, Xe2, and Xe1 cavities inFigure 2B.

Mentions: Met37 Mutants: Met37 is in the heme pocket. M37V and M37F were investigated how Met37 mutations affect oxygen escape. Several escape pathways were identified in M37V (Figure 3c andFigure 5a). Five oxygen molecules escaped between G and H helices, three between C and G helices, two between A and F helices, and one each at the FG corner and between the C and E helices. Two oxygen molecules failed to escape, and one oxygen molecule rapidly went into the A subunit from the B subunit before crossing back over again and exiting the protein. The crossing was near Phe97. Lastly, the M37V mutation resulted in a larger B cavity, causing the oxygen molecules to spend more time in this cavity. In addition, movement along the Xe4 and Xe2 cavities was increased, while movement along the Xe1 cavity was nearly absent. There is also a novel cavity in M37V lined by the residues Gly46, Thr47, Lys113, and Ile114. One oxygen molecule was present in this cavity prior to crossing over to the other subunit and subsequently exiting between the G and H helices near the novel cavity.


Effects of mutations on the molecular dynamics of oxygen escape from the dimeric hemoglobin of Scapharca inaequivalvis.

Trujillo K, Papagiannopoulos T, Olsen KW - F1000Res (2015)

A. M37V trajectories showing the internal cavities used for oxygen escape.B. M37F trajectories reveal the internal cavities for ligand transport. The relative position of each internal cavity can be compared to the B, Xe4, Xe2, and Xe1 cavities inFigure 2B.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4376171&req=5

f5: A. M37V trajectories showing the internal cavities used for oxygen escape.B. M37F trajectories reveal the internal cavities for ligand transport. The relative position of each internal cavity can be compared to the B, Xe4, Xe2, and Xe1 cavities inFigure 2B.
Mentions: Met37 Mutants: Met37 is in the heme pocket. M37V and M37F were investigated how Met37 mutations affect oxygen escape. Several escape pathways were identified in M37V (Figure 3c andFigure 5a). Five oxygen molecules escaped between G and H helices, three between C and G helices, two between A and F helices, and one each at the FG corner and between the C and E helices. Two oxygen molecules failed to escape, and one oxygen molecule rapidly went into the A subunit from the B subunit before crossing back over again and exiting the protein. The crossing was near Phe97. Lastly, the M37V mutation resulted in a larger B cavity, causing the oxygen molecules to spend more time in this cavity. In addition, movement along the Xe4 and Xe2 cavities was increased, while movement along the Xe1 cavity was nearly absent. There is also a novel cavity in M37V lined by the residues Gly46, Thr47, Lys113, and Ile114. One oxygen molecule was present in this cavity prior to crossing over to the other subunit and subsequently exiting between the G and H helices near the novel cavity.

Bottom Line: Locally enhanced sampling molecular dynamics are used here to suggest alternative pathways in the wild-type and six mutant proteins.In most cases the point mutations change the selection of exit routes observed in the simulations.Exit via the histidine gate is rarely seem although oxygen molecules do occasionally cross over the interface from one subunit to the other.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, IL, 60660, USA.

ABSTRACT
Like many hemoglobins, the structure of the dimeric hemoglobin from the clam Scapharca inaequivalvis is a "closed bottle" since there is no direct tunnel from the oxygen binding site on the heme to the solvent.  The proximal histidine faces the dimer interface, which consists of the E and F helicies.  This is significantly different from tetrameric vertebrate hemoglobins and brings the heme groups near the subunit interface. The subunit interface is also characterized by an immobile, hydrogen-bonded network of water molecules.  Although there is data which is consistent with the histidine gate pathway for ligand escape, these aspects of the structure would seem to make that pathway less likely. Locally enhanced sampling molecular dynamics are used here to suggest alternative pathways in the wild-type and six mutant proteins. In most cases the point mutations change the selection of exit routes observed in the simulations. Exit via the histidine gate is rarely seem although oxygen molecules do occasionally cross over the interface from one subunit to the other. The results suggest that changes in flexibility and, in some cases, creation of new cavities can explain the effects of the mutations on ligand exit paths.

No MeSH data available.


Related in: MedlinePlus