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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.

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Populations of tertiary states of the α (black) and β (grey) subunits as a function of quaternary state (T/R) and the HC3 protonation.The tertiary states were computed from the projections of the subunit structures during simulation onto the tertiary difference vectors connecting the T and R tertiary X-ray structures, denoted by t and r. The projections were normalized such that the r and t tertiary structure correspond to a projection of −1 and +1, respectively. A simulation frame was assigned to the R or to the T quaternary structure, if the projection onto the vector connecting the R and T quaternary states was <−0.5 or >+0.5, respectively (compare Fig. 5). Populations in Hb simulations without deprotonated His(β)146 are denoted by ‘T/R no HC3’ (A/B), and simulations with protonated His(β)146 are denoted by ‘T/R HC3’ (C/D).
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pcbi-1000774-g007: Populations of tertiary states of the α (black) and β (grey) subunits as a function of quaternary state (T/R) and the HC3 protonation.The tertiary states were computed from the projections of the subunit structures during simulation onto the tertiary difference vectors connecting the T and R tertiary X-ray structures, denoted by t and r. The projections were normalized such that the r and t tertiary structure correspond to a projection of −1 and +1, respectively. A simulation frame was assigned to the R or to the T quaternary structure, if the projection onto the vector connecting the R and T quaternary states was <−0.5 or >+0.5, respectively (compare Fig. 5). Populations in Hb simulations without deprotonated His(β)146 are denoted by ‘T/R no HC3’ (A/B), and simulations with protonated His(β)146 are denoted by ‘T/R HC3’ (C/D).

Mentions: The populations of the tertiary states r and t within each of the quaternary states R and T, as derived from the MD simulations, are presented in Fig. 7. The figure plots the probability distributions of the projections of the α (black) and β (grey) subunits onto the difference vector connecting the r and t X-ray structures. In line with Fig. 5, the projections in Fig. 7 are normalized such that −1 and +1 correspond to r and t, respectively. A simulation frame has been assigned to the R or T quaternary state, if the projection onto the difference vector connecting the R and T X-ray structures was smaller −0.5 or larger +0.5, respectively (where projections of −1 and +1 again correspond to the R and T quaternary state, respectively). The analysis has been carried out for simulations of Hb with deprotonated His(β)146 (Fig. 7A/B) and for simulations with protonated His(β)146 (Fig. 7C/D).


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)

Populations of tertiary states of the α (black) and β (grey) subunits as a function of quaternary state (T/R) and the HC3 protonation.The tertiary states were computed from the projections of the subunit structures during simulation onto the tertiary difference vectors connecting the T and R tertiary X-ray structures, denoted by t and r. The projections were normalized such that the r and t tertiary structure correspond to a projection of −1 and +1, respectively. A simulation frame was assigned to the R or to the T quaternary structure, if the projection onto the vector connecting the R and T quaternary states was <−0.5 or >+0.5, respectively (compare Fig. 5). Populations in Hb simulations without deprotonated His(β)146 are denoted by ‘T/R no HC3’ (A/B), and simulations with protonated His(β)146 are denoted by ‘T/R HC3’ (C/D).
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Related In: Results  -  Collection

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pcbi-1000774-g007: Populations of tertiary states of the α (black) and β (grey) subunits as a function of quaternary state (T/R) and the HC3 protonation.The tertiary states were computed from the projections of the subunit structures during simulation onto the tertiary difference vectors connecting the T and R tertiary X-ray structures, denoted by t and r. The projections were normalized such that the r and t tertiary structure correspond to a projection of −1 and +1, respectively. A simulation frame was assigned to the R or to the T quaternary structure, if the projection onto the vector connecting the R and T quaternary states was <−0.5 or >+0.5, respectively (compare Fig. 5). Populations in Hb simulations without deprotonated His(β)146 are denoted by ‘T/R no HC3’ (A/B), and simulations with protonated His(β)146 are denoted by ‘T/R HC3’ (C/D).
Mentions: The populations of the tertiary states r and t within each of the quaternary states R and T, as derived from the MD simulations, are presented in Fig. 7. The figure plots the probability distributions of the projections of the α (black) and β (grey) subunits onto the difference vector connecting the r and t X-ray structures. In line with Fig. 5, the projections in Fig. 7 are normalized such that −1 and +1 correspond to r and t, respectively. A simulation frame has been assigned to the R or T quaternary state, if the projection onto the difference vector connecting the R and T X-ray structures was smaller −0.5 or larger +0.5, respectively (where projections of −1 and +1 again correspond to the R and T quaternary state, respectively). The analysis has been carried out for simulations of Hb with deprotonated His(β)146 (Fig. 7A/B) and for simulations with protonated His(β)146 (Fig. 7C/D).

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