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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

The interface of the F97V mutant showing the interfacial water molecules that are still present after 10 ns of simulation.
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f7: The interface of the F97V mutant showing the interfacial water molecules that are still present after 10 ns of simulation.

Mentions: Crystallographic and molecular dynamics studies have revealed that a water cluster of 17 molecules at the interface rearrange in the ligated structure that could serve to enhance vibrational energy transport between subunits29–32. The stable interface interactions can be viewed as a means of transferring information and enhancing intra-subunit communication. We were able to confirm that the existence of a stable, hydrogen bonded water network within the subunit interface. This network is not destroyed by the mutations presented here. For example, at least ten water molecules stayed in the interface throughout the simulation for the F97V mutant (Figure 7). Although the F97V had a particularly stable hydrogen-bonded water network, similar networks are found in the other proteins also. The existence of such a stable water network may explain why the oxygen molecules were not observed leaving the dimer through the interface rather than towards the bulk solvent. We did observe oxygen molecules crossing between subunit in many of our simulations. This, however, is a much rarer event in the LESMD simulations than escape between pairs of helices. The stable hydrogen bonding network of the interfacial water molecules may provide a tunnel for directing ligands across the interface. LESMD and other studies have demonstrated that globins are known to use tunnels to enhance ligand transport31,33,34.


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)

The interface of the F97V mutant showing the interfacial water molecules that are still present after 10 ns of simulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: The interface of the F97V mutant showing the interfacial water molecules that are still present after 10 ns of simulation.
Mentions: Crystallographic and molecular dynamics studies have revealed that a water cluster of 17 molecules at the interface rearrange in the ligated structure that could serve to enhance vibrational energy transport between subunits29–32. The stable interface interactions can be viewed as a means of transferring information and enhancing intra-subunit communication. We were able to confirm that the existence of a stable, hydrogen bonded water network within the subunit interface. This network is not destroyed by the mutations presented here. For example, at least ten water molecules stayed in the interface throughout the simulation for the F97V mutant (Figure 7). Although the F97V had a particularly stable hydrogen-bonded water network, similar networks are found in the other proteins also. The existence of such a stable water network may explain why the oxygen molecules were not observed leaving the dimer through the interface rather than towards the bulk solvent. We did observe oxygen molecules crossing between subunit in many of our simulations. This, however, is a much rarer event in the LESMD simulations than escape between pairs of helices. The stable hydrogen bonding network of the interfacial water molecules may provide a tunnel for directing ligands across the interface. LESMD and other studies have demonstrated that globins are known to use tunnels to enhance ligand transport31,33,34.

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