Limits...
Spontaneous quaternary and tertiary T-R transitions of human hemoglobin in molecular dynamics simulation.

Hub JS, Kubitzki MB, de Groot BL - PLoS Comput. Biol. (2010)

Bottom Line: Using the mutual information as correlation measure, we find that the beta subunits are substantially more strongly linked to the quaternary transition than the alpha subunits.In addition, the tertiary populations of the alpha and beta subunits differ substantially, with the beta subunits showing a tendency towards R, and the alpha subunits showing a tendency towards T.Based on the simulation results, we present a transition pathway for coupled quaternary and tertiary transitions between the R and T conformations of Hb.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.

ABSTRACT
We present molecular dynamics simulations of unliganded human hemoglobin (Hb) A under physiological conditions, starting from the R, R2, and T state. The simulations were carried out with protonated and deprotonated HC3 histidines His(beta)146, and they sum up to a total length of 5.6 micros. We observe spontaneous and reproducible T-->R quaternary transitions of the Hb tetramer and tertiary transitions of the alpha and beta subunits, as detected from principal component projections, from an RMSD measure, and from rigid body rotation analysis. The simulations reveal a marked asymmetry between the alpha and beta subunits. Using the mutual information as correlation measure, we find that the beta subunits are substantially more strongly linked to the quaternary transition than the alpha subunits. In addition, the tertiary populations of the alpha and beta subunits differ substantially, with the beta subunits showing a tendency towards R, and the alpha subunits showing a tendency towards T. Based on the simulation results, we present a transition pathway for coupled quaternary and tertiary transitions between the R and T conformations of Hb.

Show MeSH

Related in: MedlinePlus

Schematic representation of consensus transition pathways between the R and T state as derived from the MD simulations.The large sphere and square depict the quaternary R and T states, respectively, whereas the small spheres and squares depict tertiary r and t states, respectively. A square with round corners indicates an intermediate structure between R and T or between r and t.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2865513&req=5

pcbi-1000774-g008: Schematic representation of consensus transition pathways between the R and T state as derived from the MD simulations.The large sphere and square depict the quaternary R and T states, respectively, whereas the small spheres and squares depict tertiary r and t states, respectively. A square with round corners indicates an intermediate structure between R and T or between r and t.

Mentions: We have analyzed the correlation between the quaternary and tertiary conformational transitions during six independent T→R transitions, as measured from the mutual information. The analysis shows that, during the T→R transition, the β subunits are substantially stronger coupled to the quaternary transition than the α subunits. The internal transitions of the four subunits seem relatively uncorrelated, with the exception of a slight correlation between the β subunits, which may however originate from the coupling from each of the β subunits to the quaternary transition, rather than from a direct coupling between the β1 and β2 subunits. Together with the tertiary distributions in a given quaternary state (Fig. 7), these results allow one to extract a consensus T-R transition pathway from the simulations, as shown in Fig. 8. Squares in Fig. 8 stand for T/t structures, circles for R/r structures, and squares with round corners for intermediate structures between T/t and R/r. We stress that these symbols represent structural similarity to the X-ray structures (or between them), and may not be equivalent to the low-affinity and high-affinity states present in solution. In simulations starting from the T X-ray structure (top in Fig. 8), two possible pathways towards the quaternary R structure were observed. (a) A partial quaternary T→R transition simultaneously to a full t→r transition of the β subunits, or (b), a full T→R transition simultaneously to a partial t→r transition of the β subunits. Subsequently, the remaining quaternary transition (c) or the remaining tertiary transition of the β subunits was found to occur (d). The transitions of the two β subunits frequently occurred time-delayed to each other, rationalizing the low mutual information between the tertiary transitions of the two β subunits (Fig. 6B). Thus, an intermediate pathway between (a/c) and (b/d) is not excluded, with the transition of β1 being completed simultaneously to a partial quaternary transition (Fig. 5C), and the transition of the β2 subunit completed simultaneously to the remaining quaternary transition (Fig. 5D). The remaining t→r transition of the α subunits was typically not observed or occurred only partly during the simulations (e.g. Fig. 5A). In simulations starting from R (bottom of Fig. 8), the α subunits carried out a partial or full tertiary transition to t without a quaternary transition. Although we did not observe full R-R2 transitions within simulation time, simulations starting from R and R2 sample common configurational space (e.g., Fig. 2A/C and S2C), suggesting that R is in thermal equilibrium with R2.


Spontaneous quaternary and tertiary T-R transitions of human hemoglobin in molecular dynamics simulation.

Hub JS, Kubitzki MB, de Groot BL - PLoS Comput. Biol. (2010)

Schematic representation of consensus transition pathways between the R and T state as derived from the MD simulations.The large sphere and square depict the quaternary R and T states, respectively, whereas the small spheres and squares depict tertiary r and t states, respectively. A square with round corners indicates an intermediate structure between R and T or between r and t.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865513&req=5

pcbi-1000774-g008: Schematic representation of consensus transition pathways between the R and T state as derived from the MD simulations.The large sphere and square depict the quaternary R and T states, respectively, whereas the small spheres and squares depict tertiary r and t states, respectively. A square with round corners indicates an intermediate structure between R and T or between r and t.
Mentions: We have analyzed the correlation between the quaternary and tertiary conformational transitions during six independent T→R transitions, as measured from the mutual information. The analysis shows that, during the T→R transition, the β subunits are substantially stronger coupled to the quaternary transition than the α subunits. The internal transitions of the four subunits seem relatively uncorrelated, with the exception of a slight correlation between the β subunits, which may however originate from the coupling from each of the β subunits to the quaternary transition, rather than from a direct coupling between the β1 and β2 subunits. Together with the tertiary distributions in a given quaternary state (Fig. 7), these results allow one to extract a consensus T-R transition pathway from the simulations, as shown in Fig. 8. Squares in Fig. 8 stand for T/t structures, circles for R/r structures, and squares with round corners for intermediate structures between T/t and R/r. We stress that these symbols represent structural similarity to the X-ray structures (or between them), and may not be equivalent to the low-affinity and high-affinity states present in solution. In simulations starting from the T X-ray structure (top in Fig. 8), two possible pathways towards the quaternary R structure were observed. (a) A partial quaternary T→R transition simultaneously to a full t→r transition of the β subunits, or (b), a full T→R transition simultaneously to a partial t→r transition of the β subunits. Subsequently, the remaining quaternary transition (c) or the remaining tertiary transition of the β subunits was found to occur (d). The transitions of the two β subunits frequently occurred time-delayed to each other, rationalizing the low mutual information between the tertiary transitions of the two β subunits (Fig. 6B). Thus, an intermediate pathway between (a/c) and (b/d) is not excluded, with the transition of β1 being completed simultaneously to a partial quaternary transition (Fig. 5C), and the transition of the β2 subunit completed simultaneously to the remaining quaternary transition (Fig. 5D). The remaining t→r transition of the α subunits was typically not observed or occurred only partly during the simulations (e.g. Fig. 5A). In simulations starting from R (bottom of Fig. 8), the α subunits carried out a partial or full tertiary transition to t without a quaternary transition. Although we did not observe full R-R2 transitions within simulation time, simulations starting from R and R2 sample common configurational space (e.g., Fig. 2A/C and S2C), suggesting that R is in thermal equilibrium with R2.

Bottom Line: Using the mutual information as correlation measure, we find that the beta subunits are substantially more strongly linked to the quaternary transition than the alpha subunits.In addition, the tertiary populations of the alpha and beta subunits differ substantially, with the beta subunits showing a tendency towards R, and the alpha subunits showing a tendency towards T.Based on the simulation results, we present a transition pathway for coupled quaternary and tertiary transitions between the R and T conformations of Hb.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.

ABSTRACT
We present molecular dynamics simulations of unliganded human hemoglobin (Hb) A under physiological conditions, starting from the R, R2, and T state. The simulations were carried out with protonated and deprotonated HC3 histidines His(beta)146, and they sum up to a total length of 5.6 micros. We observe spontaneous and reproducible T-->R quaternary transitions of the Hb tetramer and tertiary transitions of the alpha and beta subunits, as detected from principal component projections, from an RMSD measure, and from rigid body rotation analysis. The simulations reveal a marked asymmetry between the alpha and beta subunits. Using the mutual information as correlation measure, we find that the beta subunits are substantially more strongly linked to the quaternary transition than the alpha subunits. In addition, the tertiary populations of the alpha and beta subunits differ substantially, with the beta subunits showing a tendency towards R, and the alpha subunits showing a tendency towards T. Based on the simulation results, we present a transition pathway for coupled quaternary and tertiary transitions between the R and T conformations of Hb.

Show MeSH
Related in: MedlinePlus